Cyclopropane amides and analogs exhibiting anti-cancer and anti-proliferative activities

ABSTRACT

Compounds of the present invention find utility in the treatment of mammalian cancers and especially human cancers including, but not limited to, malignant melanomas, solid tumors, glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breast cancers, kidney cancers, hepatic cancers, cervical carcinomas, metastasis of primary tumor sites, myeloproliferative diseases, chronic myelogenous leukemia, leukemias, papillary thyroid carcinoma, non-small cell lung cancer, mesothelioma, hypereosinophilia syndrome, gastrointestinal stromal tumors, colonic cancers, ocular diseases characterized by hyperproliferation leading to blindness including various retinopathies, diabetic retinopathy, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, mastocytosis, mast cell leukemia, and diseases caused by PDGFR-α kinase, PDGFR-β kinase, c-KIT kinase, cFMS kinase, c-MET kinase, and oncogenic forms, aberrant fusion proteins and polymorphs of any of the foregoing kinases.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. patent applicationSer. No. 12/608,578, filed on Oct. 29, 2009, which in turn claims thebenefit of U.S. Provisional Application No. 61/109,309 filed Oct. 29,2008, each of which is incorporated by reference herein in theirentireties.

FIELD OF THE INVENTION

The present invention relates to novel kinase inhibitors and modulatorcompounds useful for the treatment of various diseases. Moreparticularly, the invention is concerned with such compounds, methods oftreating diseases, and methods of synthesis of the compounds.Preferably, the compounds are useful for the modulation of kinaseactivity of VEGFR-2 (KDR), c-MET, FLT-3c-KIT, PDGFRα, PDGFRβ, c-FMSkinase, and disease causing polymorphs and fusion proteins thereof.

BACKGROUND OF THE INVENTION

Several members of the protein kinase family have been clearlyimplicated in the pathogenesis of various proliferative andmyeloproliferative diseases and thus represent important targets fortreatment of these diseases. Some of the proliferative diseases relevantto this invention include cancer, rheumatoid arthritis, atherosclerosis,and retinopathies. Important examples of kinases which have been shownto cause or contribute to the pathogensis of these diseases includec-ABL kinase and the oncogenic fusion protein BCR-ABL kinase, c-KITkinase, c-MET, FGFR kinase family, PDGF receptor kinase, VEGF receptorkinases, FLT kinase family, the HER family and the cFMS kinase family.When such kinases are implicated in human disease, a kinase may presentas an amplified kinase (i.e. overexpression of HER1 or HER2), a mutatedkinase (i.e. c-KIT D816V) or an aberrant fusion protein (i.e. BCR-ABL).

c-KIT (KIT, CD 117, stem cell factor receptor) is a 145 kDatransmembrane tyrosine kinase protein that acts as a type-III receptor(Pereira et al. J Carcin. (2005), 4: 19). The c-KIT proto-oncogene,located on chromosome 4q11-21, encodes the c-KIT receptor, whose ligandis the stem cell factor (SCF, steel factor, kit ligand, mast cell growthfactor, Morstyn G, et al. Oncology (1994) 51(2):205; Yarden Y, et al.Embo J (1987) 6(11):3341). The receptor has tyrosine-protein kinaseactivity and binding of the ligands leads to the autophosphorylation ofKIT and its association with substrates such as phosphatidylinositol3-kinase (PI3K). Tyrosine phosphorylation by protein tyrosine kinases isof particular importance in cellular signalling and can mediate signalsfor major cellular processes, such as proliferation, survival,differentiation, apoptosis, attachment, invasiveness and migration.Defects in KIT are a cause of piebaldism, an autosomal dominant geneticdevelopmental abnormality of pigmentation characterized by congenitalpatches of white skin and hair that lack melanocytes. Gain-of-functionmutations of the c-KIT gene and the expression of phosphorylated KIT arefound in most gastrointestinal stromal tumors and mastocytosis. Further,almost all gonadal seminomas/dysgerminomas exhibit KIT membranousstaining, and several reports have clarified that some (10-25%) have ac-KIT gene mutation (Sakuma, Y. et al. Cancer Sci (2004) 95(9): 716).KIT defects have also been associated with testicular tumors includinggerm cell tumors (GCT) and testicular germ cell tumors (TGCT).

The role of c-KIT expression has been studied in hematologic and solidtumours, such as acute leukemias (Cortes J. et al. Cancer (2003) 97(11):2760) and gastrointestinal stromal tumors (GIST, Fletcher J. et al. HumPathol (2002) 33(5): 459). The clinical importance of c-KIT expressionin malignant tumors relies on studies with Gleevec® (imatinib mesylate,STI571, Novartis Pharma AG Basel, Switzerland) that specificallyinhibits tyrosine kinase receptors (Lefevre G. et al. J Biol Chem (2004)279(30): 31769). Moreover, a clinically relevant breakthrough has beenthe finding of anti-tumor effects of this compound in GIST, a group oftumors regarded as being generally resistant to conventionalchemotherapy (de Silva CM, Reid R Pathol Oncol Res (2003) 9(1): 13-19).GIST most often become Gleevec resistant and molecularly targeted smalltherapies that target c-KIT secondary mutations remain elusive.

c-MET is a unique receptor tyrosine kinase (RTK) located on chromosome7p and activated via its natural ligand hepatocyte growth factor. c-METis found mutated in a variety of solid tumors (Ma P. C. et al. CancerMetastasis (2003) 22: 309). Mutations in the tyrosine kinase domain areassociated with hereditary papillary renal cell carcinomas (Schmidt L etal. Nat. Genet. (1997)16: 68; Schmidt L, et al. Oncogene (1999) 18:2343), whereas mutations in the sema and juxtamembrane domains are oftenfound in small cell lung cancers (Ma P. C. et al. Cancer Res (2003) 63:6272). Many activating mutations are also found in breast cancers(Nakopoulou et al. Histopath (2000) 36(4): 313). The panoply of tumortypes for which c-MET mediated growth has been implicated suggests thisis a target ideally suited for modulation by specific c-MET smallmolecule inhibitors.

The TPR-MET oncogene is a transforming variant of the c-MET RTK and wasinitially identified after treatment of a human osteogenic sarcoma cellline transformed by the chemical carcinogenN-methyl-N-nitro-N-nitrosoguanidine (Park M. et al. Cell (1986) 45:895). The TPR-MET fusion oncoprotein is the result of a chromosomaltranslocation, placing the TPR3 locus on chromosome 1 upstream of aportion of the c-MET gene on chromosome 7 encoding only for thecytoplasmic region. Studies suggest that TPR-MET is detectable inexperimental cancers (e.g. Yu J. et al. Cancer (2000) 88: 1801).Dimerization of the M_(r) 65,000 TPR-MET oncoprotein through a leucinezipper motif encoded by TPR leads to constitutive activation of thec-MET kinase (Zhen Z. et al. Oncogene (1994) 9: 1691). TPR-MET activateswild-type c-MET RTK and can activate crucial cellular growth pathways,including the Ras pathway (Aklilu F. et al. Am J Physiol (1996) 271:E277) and the phosphatidylinositol 3-kinase (PI3K)/AKT pathway (PonzettoC. et al. Mol Cell Biol (1993) 13: 4600). Conversely, in contrast toc-MET RTK, TPR-MET is ligand independent, lacks the CBL-like SH2 domainbinding site in the juxtamembrane region in c-MET, and is mainlycytoplasmic. c-MET immunohistochemical expression seems to be associatedwith abnormal β-catenin expression, a hallmark feature of epithelial tomesynchemal transition (EMT) and provides good prognostic and predictivefactors in breast cancer patients.

The majority of small molecule kinase inhibitors that have been reportedhave been shown to bind in one of three ways. Most of the reportedinhibitors interact with the ATP binding domain of the active site andexert their effects by competing with ATP for occupancy. Otherinhibitors have been shown to bind to a separate hydrophobic region ofthe protein known as the “DFG-in-conformation” pocket wherein such abinding mode by the inhibitor causes the kinase to adopt the “DM-out”conformation, and still others have been shown to bind to both the ATPdomain and the “DFG-in-conformation” pocket again causing the kinase toadopt the “DGF-out” conformation. Examples that induce the kinase toadopt the “DGF-out” conformation can be found in Lowinger et al, CurrentPharmaceutical Design (2002) δ: 2269; Dumas, J. et al., Current Opinionin Drug Discovery & Development (2004) 7: 600; Dumas, J. et al, WO2003068223 A1 (2003); Dumas, J., et al, WO 9932455 A1 (1999), and Wan,P. T. C., et al, Cell (2004) 116: 855.

Physiologically, kinases are regulated by a commonactivation/deactivation mechanism wherein a specific activation loopsequence of the kinase protein binds into a specific pocket on the sameprotein which is referred to as the switch control pocket. Such bindingoccurs when specific amino acid residues of the activation loop aremodified for example by phosphorylation, oxidation, or nitrosylation.The binding of the activation loop into the switch pocket results in aconformational change of the protein into its active form (Huse, M. andKuriyan, J. Cell (2002) 109: 275).

SUMMARY OF THE INVENTION

Compounds of the present invention find utility in the treatment ofmammalian cancers and especially human cancers including, but notlimited to, solid tumors, melanomas, glioblastomas, ovarian cancer,pancreatic cancer, prostate cancer, lung cancers, breast cancers, kidneycancers, cervical carcinomas, metastasis of primary tumor sites,myeloproliferative diseases, leukemias, papillary thyroid carcinoma, nonsmall cell lung cancer, mesothelioma, hypereosinophilic syndrome,gastrointestinal stromal tumors, colonic cancers, ocular diseasescharacterized by hyperproliferation leading to blindness includingvarious retinopathies, rheumatoid arthritis, asthma, chronic obstructivepulmonary disorder, mastocyclosis, mast cell leukemia, and diseasescaused by PDGFR-α kinase, PDGFR-β kinase, c-KIT kinase, cFMS kinase,c-MET kinase, and oncogenic forms, aberrant fusion proteins andpolymorphs of any of the foregoing kinases.

In a first aspect, compounds the formula Ia are described herein:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, andtautomers thereof;wherein Q1, Q2, and Q3, are each individually and independently selectedfrom the group consisting of N and CH and wherein at least one of Q1 andQ2 are N;and wherein the ring containing Q1 and Q2 may be optionally substitutedwith (R20)_(x) moieties;each D is individually taken from the group consisting of C, CH, C—R20,N—Z3, N, and O, such that the resultant ring is taken from the groupconsisting of pyrazolyl, isoxazolyl, triazolyl and imidazolyl;and wherein the ring containing Q3 may be optionally substituted withone to three R16 moieties;

V is NR4, or

each Q5 is C(Z2B)₂;W is a direct bond, —[C(R13)R14]_(m)-, —[C(R13)R14]_(m)NR4-, or NR4;A is selected from the group consisting of indanyl, tetrahydronapthyl,thienyl, phenyl, naphthyl, pyrazinyl, pyridazinyl, triazinyl, pyridinyl,and pyrimidinyl;

X2 is —O—;

when A has one or more substitutable sp2-hybridized carbon atoms, eachrespective sp2 hybridized carbon atom may be optionally substituted witha Z1B substituent;when A has one or more substitutable sp3-hybridized carbon atoms, eachrespective sp3 hybridized carbon atom may be optionally substituted witha Z2B substituent;each Z1B is independently and individually selected from the groupconsisting of hydrogen, C1-6alkyl, branched C3-C7alkyl, halogen,fluoroC1-C6alkyl wherein the alkyl moiety can be partially or fullyfluorinated, C1-C6alkoxy, fluoroC1-C6alkoxy wherein the alkyl moiety canbe partially or fully fluorinated, and —(CH₂)_(n)CN;each Z2B is independently and individually selected from the groupconsisting of hydrogen, C1-C6alkyl, and branched C3-C7alkyl;each Z3 is independently and individually selected from the groupconsisting of hydrogen, C1-C6alkyl, branched C3-C7alkyl,C3-C8cycloalkyl, fluoroC1-C6alkyl wherein the alkyl moiety can bepartially or fully fluorinated, hydroxyC2-C6alkyl-, R5C(O)(CH₂)_(n)—,(R4)₂NC(O)C1-C6alkyl-, R8C(O)N(R4)(CH₂)_(q)—, —(CH₂)_(q)CN,—(CH₂)_(q)R5, and —(CH₂)_(q)N(R4)₂;each R2 is selected from the group consisting of hydrogen,R17-substituted aryl-, C1-C6alkyl, branched C3-C8alkyl, R19 substitutedC3-C8cycloalkyl-, and fluoroC1-C6alkyl- wherein the alkyl is fully orpartially fluorinated;each R3 is independently and individually selected from the groupconsisting of hydrogen, C1-C6alkyl, branched C3-C7alkyl, andC3-C8cycloalkyl;each R4 is independently and individually selected from the groupconsisting of hydrogen, C1-C6alkyl, hydroxyC1-C6alkyl-,dihydroxyC1-C6alkyl-, C1-C6alkoxyC1-C6alkyl-, branched C3-C7alkyl,hydroxyl substituted branched C3-C6alkyl-, C1-C6alkoxy branchedC3-C6alkyl-, dihydroxy substituted branched C3-C6alkyl-,—(CH₂)_(p)N(R7)₂, —(CH₂)_(p)R5, —(CH₂)_(p)C(O)N(R7)₂, —(CH₂)_(n)C(O)R5,—(CH₂)_(n)C(O)OR3, and R19 substituted C3-C8cycloalkyl-;each R5 is independently and individually selected from the groupconsisting of

and wherein the symbol (##) is the point of attachment to respective R4,R7, R8, R20 or Z3 moieties containing a R5 moiety;each R7 is independently and individually selected from the groupconsisting of hydrogen, C1-C6alkyl, hydroxyC2-C6alkyl-,dihydroxyC2-C6alkyl-, C1-C6alkoxyC2-C6alkyl-, branched C3-C7alkyl,hydroxy substituted branched C3-C6alkyl-, C1-C6alkoxy branchedC3-C6alkyl-, dihydroxy substituted branched C3-C6alkyl-, —(CH₂)_(q)R5,—(CH₂)_(n)C(O)R5, —(CH₂)_(n)C(O)OR3, R19 substituted C3-C8cycloalkyl-and —(CH₂)_(n)R17;each R8 is independently and individually selected from the groupconsisting of C1-C6alkyl, branched C3-C7alkyl, fluoroC1-C6alkyl- whereinthe alkyl moiety is partially or fully fluorinated, R19 substitutedC3-C8cycloalkyl-, phenyl, phenylC1-C6alkyl-, OH, C1-C6alkoxy, —N(R3)₂,—N(R4)₂, and R5;each R10 is independently and individually selected from the groupconsisting of —CO₂H, —CO₂C1-C6alkyl, —C(O)N(R4)₂, OH, C1-C6alkoxy, and—N(R4)₂;R13 and R14 are each individually and independently selected from thegroup consisting of hydrogen, C1-C6alkyl, branched C3-C8alkyl,fluoroC1-C6alkyl- wherein the alkyl is fully or partially fluorinated,hydroxyl substituted C1-C6alkyl-, C1-C6alkoxy substituted C1-C6alkyl-,hydroxyl substituted branched C3-C8alkyl-, and alkoxy substitutedbranched C3-C8alkyl;each R16 is independently and individually selected from the groupconsisting of hydrogen, C1-C6alkyl, branched C3-C7alkyl, R19 substitutedC3-C8cycloalkyl-, halogen, fluoroC1-C6alkyl- wherein the alkyl moietycan be partially or fully fluorinated, cyano, hydroxyl, C1-C6alkoxy,fluoroC1-C6alkoxy- wherein the alkyl moiety can be partially or fullyfluorinated, —N(R3)₂, —N(R4)₂, R3 substituted C2-C3alkynyl- and nitro;each R17 is independently and individually selected from the groupconsisting of hydrogen, C1-C6alkyl, branched C3-C7alkyl,hydroxyC2-C6alkyl-, R19 substituted C3-C8cycloalkyl-, halogen,fluoroC1-C6alkyl- wherein the alkyl moiety can be partially or fullyfluorinated, cyano, hydroxyl, C1-C6alkoxy, fluoroC1-C6alkoxy- whereinthe alkyl moiety can be partially or fully fluorinated, —N(R3)₂,—N(R4)₂, and nitro;each R19 is independently and individually selected from the groupconsisting of hydrogen, OH and C1-C6alkyl;each R20 is independently and individually selected from the groupconsisting of hydrogen, C1-C6alkyl, branched C3-C7alkyl, R19 substitutedC3-C8cycloalkyl-, halogen, fluoroC1-C6alkyl- wherein the alkyl moietycan be partially or fully fluorinated, cyano, hydroxyl,hydroxyC1-C6alkyl-, C1-C6alkoxyC1-C6alkyl-, C1-C6alkoxy,fluoroC1-C6alkoxy- wherein the alkyl moiety can be partially or fullyfluorinated, —N(R3)₂, —N(R4)₂, —(CH₂)_(n)R5, —(CH₂)_(n)N(R3)C(O)R3,—(CH₂)_(n)C(O)N(R3)₂ and nitro;each m is independently and individually 1-3, each n is independentlyand individually 0-6; each p is independently and individually 1-4; eachq is independently and individually 2-6; each v is independently andindividually 1 or 2; each x is independently and individually 0-2;stereoisomers, regioisomers and tautomers of such compounds.

In some embodiments,

is selected from the group consisting ofwherein the symbol (**) indicates the point of attachment to theheteroaryl Q1, Q2 containing ring.

In another embodiment, the compounds have formula Ib

In another embodiment, the compounds have formula Ic

In another embodiment, the compounds have formula Id

In another embodiment, the compounds have formula Ie

In another embodiment, the compounds have formula If

In another embodiment, the compounds have formula Ig

In another embodiment, the compounds have formula Ih

In another embodiment, the compounds have formula Ii

In another embodiment, the compounds have formula Ij

In another embodiment, the compounds have formula Ik

In another embodiment, the compounds have formula Il

In another embodiment, the compounds have formula Im

In another embodiment, the compounds have formula In

In another embodiment, the compounds have formula Io

In another embodiment, the compounds have formula Ip

In another embodiment, the compounds have formula Iq

In another embodiment, the compounds have formula Ir

In another embodiment, the compounds have formula Is

In another embodiment, the compounds have formula It

In another embodiment, the compounds have formula Iu

In another embodiment, the compounds have formula Iv

In another embodiment, the compounds have formula Iw

In another embodiment, the compounds have formula Ix

In another embodiment, the compounds have formula Iy

In another embodiment, the compounds have formula Iz

In another embodiment, the compounds have formula Iaa

In another embodiment, the compounds have formula Ibb

In another embodiment, the compounds have formula Icc

In another embodiment, the compounds have formula Idd

In another embodiment, the compounds have formula Iee

In another embodiment, the compounds have formula Iff

In another embodiment, the compounds have formula Igg

In another embodiment, the compounds have formula Ihh

In another embodiment, the compounds have formula Iii

In another embodiment, the compounds have formula Ijj

In another embodiment, the compounds have formula Ikk

In another aspect, pharmaceutical compositions are described whichcomprise a compound of the invention, together with a pharmaceuticallyacceptable carrier, optionally containing an additive selected from thegroup consisting of adjuvants, excipients, diluents, and stabilizers.

Compounds of the present invention find utility in the treatment ofmammalian cancers, hyperproliferative diseases, metabolic diseases,neurodegenerative diseases, or diseases characterized by angiogenesisincluding, but not limited to, solid tumors, melanomas, glioblastomas,ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breastcancers, renal cancers, hepatic cancers, cervical carcinomas, metastasisof primary tumor sites, myeloproliferative diseases, chronic myelogenousleukemia, leukemias, papillary thyroid carcinoma, non-small cell lungcancer, mesothelioma, hypereosinophilic syndrome, gastrointestinalstromal tumors, colonic cancers, ocular diseases characterized byhyperproliferation leading to blindness including retinopathies,diabetic retinopathy, age-related macular degeneration andhypereosinophilic syndrome, rheumatoid arthritis, asthma, chronicobstructive pulmonary, mastocytosis, mast cell leukemia, and diseasescaused by PDGFR-α kinase, PDGFR-β kinase, c-KIT kinase, cFMS kinase,c-MET kinase, and oncogenic forms, aberrant fusion proteins andpolymorphs of any of the foregoing kinases.

In some embodiments, the kinase is c-MET protein kinase, and any fusionprotein, mutation and polymorphs thereof.

In some embodiments, the compound is administered by a method selectedfrom the group consisting of oral, parenteral, inhalation, andsubcutaneous.

SECTION 1 Detailed Description of the Invention

Throughout this disclosure, various patents, patent applications andpublications are referenced. The disclosures of these patents, patentapplications and publications in their entireties are incorporated intothis disclosure by reference in order to more fully describe the stateof the art as known to those skilled therein as of the date of thisdisclosure. This disclosure will govern in the instance that there isany inconsistency between the patents, patent applications andpublications and this disclosure.

For convenience, certain terms employed in the specification, examplesand claims are collected here. Unless defined otherwise, all technicaland scientific terms used in this disclosure have the same meanings ascommonly understood by one of ordinary skill in the art to which thisdisclosure belongs. The initial definition provided for a group or termprovided in this disclosure applies to that group or term throughout thepresent disclosure individually or as part of another group, unlessotherwise indicated.

The compounds of this disclosure include any and all possible isomers,stereoisomers, enantiomers, diastereomers, tautomers, pharmaceuticallyacceptable salts, and solvates thereof. Thus, the terms “compound” and“compounds” as used in this disclosure refer to the compounds of thisdisclosure and any and all possible isomers, stereoisomers, enantiomers,diastereomers, tautomers, pharmaceutically acceptable salts, andsolvates thereof.

The following descriptions refer to various compounds and moietiesthereof.

The term “cycloalkyl” refers to monocyclic saturated carbon rings takenfrom cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl andcyclooctanyl.

The term “alkyl” refers to straight or branched chain C1-C6alkyls.

The term “halogen” refers to fluorine, chlorine, bromine, and iodine.

The term “alkoxy” refers to —O-(alkyl) wherein alkyl is defined asabove.

The term “alkoxylalkyl” refers to -(alkyl)-O-(alkyl) wherein alkyl isdefined as above.

The term “alkoxylcarbonyl” refers to —C(O)O-(alkyl) wherein alkyl isdefined as above.

The term “carboxylC1-C6alkyl” refers to —(C1-C6alkyl)CO₂H wherein alkylis defined as above.

The term “substituted” in connection with a moiety refers to the factthat a further substituent may be attached to the moiety to anyacceptable location on the moiety.

The term “salts” embraces pharmaceutically acceptable salts commonlyused to form alkali metal salts of free acids and to form addition saltsof free bases. The nature of the salt is not critical, provided that itis pharmaceutically-acceptable. Suitable pharmaceutically-acceptableacid addition salts may be prepared from an inorganic acid or from anorganic acid. Examples of such inorganic acids are hydrochloric,hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid.Appropriate organic acids may be selected from aliphatic,cycloaliphatic, aromatic, arylaliphatic, and heterocyclyl containingcarboxylic acids and sulfonic acids, examples of which are formic,acetic, propionic, succinic, glycolic, gluconic, lactic, malic,tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic,aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic,p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic,cyclohexylaminosulfonic, algenic, 3-hydroxybutyric, galactaric andgalacturonic acid. Suitable pharmaceutically-acceptable salts of freeacid-containing compounds of Formula I include metallic salts andorganic salts. More preferred metallic salts include, but are notlimited to appropriate alkali metal (group Ia) salts, alkaline earthmetal (group IIa) salts and other physiological acceptable metals. Suchsalts can be made from aluminum, calcium, lithium, magnesium, potassium,sodium and zinc. Preferred organic salts can be made from primaryamines, secondary amines, tertiary amines and quaternary ammonium salts,including in part, tromethamine, diethylamine, tetra-N-methylammonium,N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine) and procaine.

The terms “administer”, “administering”, or “administration” as used inthis disclosure refer to either directly administering a compound orpharmaceutically acceptable salt of the compound or a composition to asubject, or administering a prodrug derivative or analog of the compoundor pharmaceutically acceptable salt of the compound or composition tothe subject, which can form an equivalent amount of active compoundwithin the subject's body.

The term “carrier”, as used in this disclosure, encompasses carriers,excipients, and diluents and means a material, composition or vehicle,such as a liquid or solid filler, diluent, excipient, solvent orencapsulating material, involved in carrying or transporting apharmaceutical agent from one organ, or portion of the body, to anotherorgan, or portion of the body.

The term “disorder” is used in this disclosure to mean, and is usedinterchangeably with, the terms disease, condition, or illness, unlessotherwise indicated.

The terms “effective amount” and “therapeutically effective amount” areused interchangeably in this disclosure and refer to an amount of acompound that, when administered to a subject, is capable of reducing asymptom of a disorder in a subject. The actual amount which comprisesthe “effective amount” or “therapeutically effective amount” will varydepending on a number of conditions including, but not limited to, theparticular disorder being treated, the severity of the disorder, thesize and health of the patient, and the route of administration. Askilled medical practitioner can readily determine the appropriateamount using methods known in the medical arts.

The terms “isolated” and “purified” as used in this disclosure refer toa component separated from other components of a reaction mixture or anatural source. In certain embodiments, the isolate contains at leastabout 50%, at least about 55%, at least about 60%, at least about 65%,at least about 70%, at least about 75%, at least about 80%, at leastabout 85%, at least about 90%, at least about 95%, or at least about 98%of the compound or pharmaceutically acceptable salt of the compound byweight of the isolate.

The phrase “pharmaceutically acceptable” is employed in this disclosureto refer to those compounds, materials, compositions, and/or dosageforms which are, within the scope of sound medical judgment, suitablefor use in contact with the tissues of human beings and animals withoutexcessive toxicity, irritation, allergic response, or other problem orcomplication, commensurate with a reasonable benefit/risk ratio.

The term “prodrug” refers to derivatives of active compounds whichrevert in vivo into the active form. For example, a carboxylic acid formof an active drug may be esterified to create a prodrug, and the esteris subsequently converted in vivo to revert to the carboxylic acid form.See Ettmayer et. al, J. Med. Chem. (2004) 47: 2393 and Lorenzi et. al,J. Pharm. Exp. Therpeutics (2005) 883 for reviews.

As used in this disclosure, the term “subject” includes, withoutlimitation, a human or an animal. Exemplary animals include, but are notlimited to, mammals such as mouse, rat, guinea pig, dog, cat, horse,cow, pig, monkey, chimpanzee, baboon, or rhesus monkey.

The term “treating” with regard to a subject, refers to improving atleast one symptom of the subject's disorder. Treating can be curing,improving, or at least partially ameliorating the disorder.

The term “hydrate” refers to a compound as described herein which isassociated with water in the molecular form, i.e., in which the H—OHbond is not split, and may be represented, for example, by the formulaR.H₂O, where R is a compound as described herein. A given compound mayform more than one hydrate including, for example, monohydrates (R.H₂O),dihydrates (R.2H₂O), trihydrates (R.3H₂O), and the like.

The term “solvate” refers to a compound of the present invention whichis associated with solvent in the molecular form, i.e. in which thesolvent is coordinatively bound, and may be represented, for example, bythe formula R.(solvent), where R is a compound of the invention. A givencompound may form more than one solvate including, for example,monosolvates (R.(solvent)) or polysolvates (R.n(solvent)) wherein n isan integer>1) including, for example, disolvates (R.2(solvent)),trisolvates (R.3(solvent)), and the like, or hemisolvates, such as, forexample, R.n/2(solvent), R.n/3(solvent), R.n/4(solvent) and the likewherein n is an integer. Solvents herein include mixed solvents, forexample, methanol/water, and as such, the solvates may incorporate oneor more solvents within the solvate.

The term “acid hydrate” refers to a complex that may be formed throughassociation of a compound having one or more base moieties with at leastone compound having one or more acid moieties or through association ofa compound having one or more acid moieties with at least one compoundhaving one or more base moieties, said complex being further associatedwith water molecules so as to form a hydrate, wherein said hydrate is aspreviously defined and R represents the complex herein described above.

Structural, chemical and stereochemical definitions are broadly takenfrom IUPAC recommendations, and more specifically from Glossary of Termsused in Physical Organic Chemistry (IUPAC Recommendations 1994) assummarized by P. Müller, Pure Appl. Chem., (1994) 66: 1077-1184 andBasic Terminology of Stereochemistry (IUPAC Recommendations 1996) assummarized by G. P. Moss Pure and Applied Chemistry, (1996) 68:2193-2222). Specific definitions are as follows:

Atropisomers are defined as a subclass of conformers which can beisolated as separate chemical species and which arise from restrictedrotation about a single bond.

Regioisomers or structural isomers are defined as isomers involving thesame atoms in different arrangements.

Enantiomers are defined as one of a pair of molecular entities which aremirror images of each other and non-superimposable.

Diastereomers or diastereoisomers are defined as stereoisomers otherthan enantiomers. Diastereomers or diastereoisomers are stereoisomersnot related as mirror images. Diastereoisomers are characterized bydifferences in physical properties, and by some differences in chemicalbehavior towards achiral as well as chiral reagents.

The term “tautomer” as used in this disclosure refers to compoundsproduced by the phenomenon wherein a proton of one atom of a moleculeshifts to another atom. (March, Advanced Organic Chemistry: Reactions,Mechanisms and Structures, 4th Ed., John Wiley & Sons, pp. 69-74(1992)).

Tautomerism is defined as isomerism of the general form

G-X—Y═Z

X═Y—Z-G

where the isomers (called tautomers) are readily interconvertible; theatoms connecting the groups X,Y,Z are typically any of C, H, O, or S,and G is a group which becomes an electrofuge or nucleofuge duringisomerization. The most common case, when the electrofuge is H⁺, is alsoknown as “prototropy”.

Tautomers are defined as isomers that arise from tautomerism,independent of whether the isomers are isolable.

ChemDraw version 8.0 or 10. (CambridgeSoft Corporation, Cambridge,Mass.) was used to name structures.

1.1 First Aspect of the Invention—Compounds, Methods, and Preparations

Compounds of the formula Ia

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, andtautomers thereof;wherein Q1, Q2, and Q3, are each individually and independently selectedfrom the group consisting of N and CH and wherein at least one of Q1 andQ2 are N;and wherein the ring containing Q1 and Q2 may be optionally substitutedwith (R20)_(x) moieties;each D is individually taken from the group consisting of C, CH, C—R20,N—Z3, N, and O, such that the resultant ring is taken from the groupconsisting of pyrazolyl, isoxazolyl, triazolyl and imidazolyl;and wherein the ring containing Q3 may be optionally substituted withone to three R16 moieties;

V is NR4, or

each Q5 is C(Z2B)₂;W is a direct bond, —[C(R13)R14]_(m), —[C(R13)R14]_(m)NR4-, or NR4;A is selected from the group consisting of indanyl, tetrahydronapthyl,thienyl, phenyl, naphthyl, pyrazinyl, pyridazinyl, triazinyl, pyridinyl,and pyrimidinyl;

X2 is —O—;

when A has one or more substitutable sp2-hybridized carbon atoms, eachrespective sp2 hybridized carbon atom may be optionally substituted witha Z1B substituent;when A has one or more substitutable sp3-hybridized carbon atoms, eachrespective sp3 hybridized carbon atom may be optionally substituted witha Z2B substituent;each Z1B is independently and individually selected from the groupconsisting of hydrogen, C1-6alkyl, branched C3-C7alkyl, halogen,fluoroC1-C6alkyl wherein the alkyl moiety can be partially or fullyfluorinated, C1-C6alkoxy, fluoroC1-C6alkoxy wherein the alkyl moiety canbe partially or fully fluorinated, and —(CH₂)_(n)CN;each Z2B is independently and individually selected from the groupconsisting of hydrogen, C1-C6alkyl, and branched C3-C7alkyl;each Z3 is independently and individually selected from the groupconsisting of hydrogen, C1-C6alkyl, branched C3-C7alkyl,C3-C8cycloalkyl, fluoroC1-C6alkyl wherein the alkyl moiety can bepartially or fully fluorinated, hydroxyC2-C6alkyl-, —R5C(O)(CH₂)_(n)—,(R4)₂NC(O)C1-C6alkyl-, R8C(O)N(R4)(CH₂)_(q)—, —(CH₂)_(q)CN,—(CH₂)_(q)R5, and —(CH₂)_(q)N(R4)₂;each R2 is selected from the group consisting of hydrogen,R17-substituted aryl-, C1-C6alkyl, branched C3-C8alkyl, R19 substitutedC3-C8cycloalkyl-, and fluoroC1-C6alkyl- wherein the alkyl is fully orpartially fluorinated;wherein each R3 is independently and individually selected from thegroup consisting of hydrogen, C1-C6alkyl, branched C3-C7alkyl, andC3-C8cycloalkyl;each R4 is independently and individually selected from the groupconsisting of hydrogen, C1-C6alkyl, hydroxyC1-C6alkyl-,dihydroxyC1-C6alkyl-, C1-C6alkoxyC1-C6alkyl-, branched C3-C7alkyl,hydroxyl substituted branched C3-C6alkyl-, C1-C6alkoxy branchedC3-C6alkyl-, dihydroxy substituted branched C3-C6alkyl-,—(CH₂)_(p)N(R7)₂, —(CH₂)_(p)R5, —(CH₂)_(p)C(O)N(R7)₂, —(CH₂)_(n)C(O)R5,—(CH₂)_(n)C(O)OR3, and R19 substituted C3-C8cycloalkyl-;each R5 is independently and individually selected from the groupconsisting of

and wherein the symbol (##) is the point of attachment to respective R4,R7, R8, R20 or Z3 moieties containing a R5 moiety;each R7 is independently and individually selected from the groupconsisting of hydrogen, C1-C6alkyl, hydroxyC2-C6alkyl-,dihydroxyC2-C6alkyl-, C1-C6alkoxyC2-C6alkyl-, branched C3-C7alkyl,hydroxy substituted branched C3-C6alkyl-, C1-C6alkoxy branchedC3-C6alkyl-, dihydroxy substituted branched C3-C6alkyl-, —(CH₂)_(q)R5,—(CH₂)_(n)C(O)R5, —(CH₂)_(n)C(O)OR3, R19 substituted C3-C8cycloalkyl-and —(CH₂)_(n)R17;each R8 is independently and individually selected from the groupconsisting of C1-C6alkyl, branched C3-C7alkyl, fluoroC1-C6alkyl- whereinthe alkyl moiety is partially or fully fluorinated, R19 substitutedC3-C8cycloalkyl-, phenyl, phenylC1-C6alkyl-, OH, C1-C6alkoxy, —N(R3)₂,—N(R4)₂, and R5;each R10 is independently and individually selected from the groupconsisting of —CO₂H, —CO₂C1-C6alkyl, —C(O)N(R4)₂, OH, C1-C6alkoxy, and—N(R4)₂;R13 and R14 are each individually and independently selected from thegroup consisting of hydrogen, C1-C6alkyl, branched C3-C8alkyl,fluoroC1-C6alkyl- wherein the alkyl is fully or partially fluorinated,hydroxyl substituted C1-C6alkyl-, C1-C6alkoxy substituted C1-C6alkyl-,hydroxyl substituted branched C3-C8alkyl-, and alkoxy substitutedbranched C3-C8alkyl;each R16 is independently and individually selected from the groupconsisting of hydrogen, C1-C6alkyl, branched C3-C7alkyl, R19 substitutedC3-C8cycloalkyl-, halogen, fluoroC1-C6alkyl- wherein the alkyl moietycan be partially or fully fluorinated, cyano, hydroxyl, C1-C6alkoxy,fluoroC1-C6alkoxy- wherein the alkyl moiety can be partially or fullyfluorinated, —N(R3)₂, —N(R4)₂, R3 substituted C2-C3alkynyl- and nitro;each R17 is independently and individually selected from the groupconsisting of hydrogen, C1-C6alkyl, branched C3-C7alkyl,hydroxyC2-C6alkyl-, R19 substituted C3-C8cycloalkyl-, halogen,fluoroC1-C6alkyl- wherein the alkyl moiety can be partially or fullyfluorinated, cyano, hydroxyl, C1-C6alkoxy, fluoroC1-C6alkoxy- whereinthe alkyl moiety can be partially or fully fluorinated, —N(R3)₂,—N(R4)₂, and nitro;each R19 is independently and individually selected from the groupconsisting of hydrogen, OH and C1-C6alkyl;each R20 is independently and individually selected from the groupconsisting of hydrogen, C1-C6alkyl, branched C3-C7alkyl, R19 substitutedC3-C8cycloalkyl-, halogen, fluoroC1-C6alkyl- wherein the alkyl moietycan be partially or fully fluorinated, cyano, hydroxyl,hydroxyC1-C6alkyl-, C1-C6alkoxyC1-C6alkyl-, C1-C6alkoxy,fluoroC1-C6alkoxy- wherein the alkyl moiety can be partially or fullyfluorinated, —N(R3)₂, —N(R4)₂, —(CH₂)_(n)R5, —(CH₂)_(n)N(R3)C(O)R3,—(CH₂)_(n)C(O)N(R3)₂ and nitro;each m is independently and individually 1-3, each n is independentlyand individually 0-6; each p is independently and individually 1-4; eachq is independently and individually 2-6; each v is independently andindividually 1 or 2; each x is independently and individually 0-2;stereoisomers, regioisomers and tautomers of such compounds.

In the aforementioned compounds of formula Ia, subscript letters arefrequently used to define variations in moiety and substituentstructure. For instance, in the case where R4 on the amide nitrogen is—(CH₂)_(n)C(O)R5, and the R20 on the Q1/Q2 ring is —(CH₂)_(n)R5, each“n” subscript can be individually and independently varied from zero tosix. For example, the situation wherein the R4 “n” subscript is 2 andthe R20 “n” subscript is 6 results in a R4 substituent of —CH₂CH₂C(O)R5and a R20 substituent of —CH₂CH₂CH₂CH₂CH₂CH₂R5 (see molecule 3 below).By extension, a subscript definition may be variably used to definedifferent moieties residing within the same compound of formula Ia.

In the case where a specific moiety (e.g. R4) is used in more than oneplace within a molecule, each instance of R4 is individually andindependently varied according to the definition of R4. As shown below,generic molecule Ia can be elaborated to “molecule “4” which has twoinstances of R4, each of which can be different (R4=H & R4=CH₃) as shownis “molecule 5”.

1.1.1 Compounds of Formula Ia which Exemplify Moieties

wherein the symbol (**) indicates the point of attachment to theheteroaryl Q1, Q2 containing ring.1.1.2 Compounds of 1.1.1 which Exemplify 01-03 Moieties

1.1.3 Compounds of 1.1.2 Having Formula Ic

1.1.4 Compounds of 1.1.2 Having Formula Id

1.1.5 Compounds of 1.1.2 Having Formula Ie

1.2 Compounds of 1.1.1 which Exemplify Q1-Q3 Moieties

1.2.1 Compounds of 1.2 Having Formula Ig

1.2.2 Compounds of 1.2 Having Formula Ih

1.2.3 Compounds of 1.2 Having Formula Ii

1.3 Compounds of 1.1 which Exemplify Q1-Q3 Moieties

1.3.1 Compounds of 1.3 Having Formula Ik

1.3.2 Compounds of 1.3 Having Formula Il

1.3.3 Compounds of 1.3 Having Formula Im

1.4 Compounds of 1.1.1 which Exemplify Q1-Q3 Moieties

1.4.1 Compounds of 1.4 Having Formula Io

1.4.2 Compounds of 1.4 Having Formula Ip

1.4.3 Compounds of 1.4 Having Formula Iq

1.5 Compounds of 1.1.1 which Exemplify Q1-Q3 Moieties

1.5.1 Compounds of 1.5 Having Formula Is

1.5.2 Compounds of 1.5 Having Formula It

1.5.3 Compounds of 1.5 Having Formula Iu

1.6 Compounds of 1.1.1 which Exemplify Q1-Q3 Moieties

1.6.1 Compounds of 1.6 Having Formula Iw

1.6.2 Compounds of 1.6 Having Formula Ix

1.6.3 Compounds of 1.6 Having Formula Iy

1.7 Compounds of 1.1.1 which Exemplify Q1-Q3 Moieties

1.7.1 Compounds of 1.7 Having Formula Iaa

1.7.2 Compounds of 1.7 Having Formula Ibb

1.7.3 Compounds of 1.7 Having Formula Icc

1.8 Compounds of 1.1.1 which Exemplify Q1-Q3 Moieties

1.8.1 Compounds of 1.8 Having Formula Iee

1.8.2 Compounds of 1.8 Having Formula Iff

1.8.3 Compounds of 1.8 Having Formula Igg

1.9 Compounds of 1.1.1 which Exemplify Q1-Q3 Moieties

1.9.1 Compounds of 1.9 Having Formula Iii

1.9.2 Compounds of 1.9 Having Formula Ijj

1.9.3 Compounds of 1.9 Having Formula Ikk

1.10 Illustrative Compounds of Formula Ia

Illustrative compounds of formula Ia include, but are not limited to,N-(2,3-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,N-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,N-benzyl-N′-(2,3-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)cyclopropane-1,1-dicarboxamide,N-benzyl-N′-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)cyclopropane-1,1-dicarboxamide,N-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-phenylcyclopropane-1,1-dicarboxamide,N-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(3-(trifluoromethyl)phenyl)cyclopropane-1,1-dicarboxamide,N-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,N-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(4-methoxyphenyl)cyclopropane-1,1-dicarboxamide,N-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(3-methoxyphenyl)cyclopropane-1,1-dicarboxamide,N-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(3-fluorophenyl)cyclopropane-1,1-dicarboxamide,N-(4-fluorophenyl)-N′-(3-methyl-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)cyclopropane-1,1-dicarboxamide,1-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea,N-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(pyridin-4-yl)cyclopropane-1,1-dicarboxamide,N-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(pyridin-3-yl)cyclopropane-1,1-dicarboxamide,N-(3-chlorobenzyl)-N′-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)cyclopropane-1,1-dicarboxamide,N-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-((S)-1-phenylethyl)cyclopropane-1,1-dicarboxamide,N-(3-fluoro-4-(2-(1-methyl-1,4-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-((R)-1-phenylethyl)cyclopropane-1,1-dicarboxamide,N-(4-fluorobenzyl)-N′-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)cyclopropane-1,1-dicarboxamide,N-(4-(2-(1-ethyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,N-(3-fluoro-4-(2-(1-propyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,N-(3-fluoro-4-(2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,N-(4-chlorophenyl)-N′-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)cyclopropane-1,1-dicarboxamide,N-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-p-tolylcyclopropane-1,1-dicarboxamide,N-(3,4-difluorophenyl)-N′-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)cyclopropane-1,1-dicarboxamide,N-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(4-(trifluoromethyl)phenyl)cyclopropane-1,1-dicarboxamide,N-(3-cyano-4-fluorophenyl)-N′-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)cyclopropane-1,1-dicarboxamide,N-(2,4-difluorophenyl)-N′-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)cyclopropane-1,1-dicarboxamide,N-(4-cyanophenyl)-N′-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)cyclopropane-1,1-dicarboxamide,N-(2-chloro-4-fluorophenyl)-N′-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)cyclopropane-1,1-dicarboxamide,N-(3-chloro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,N-(4-(2-(1H-pyrazol-4-yl)pyridin-4-yloxy)-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,N-(2-fluoro-3-methyl-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,N-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-((S)-1-(4-fluorophenyl)ethyl)cyclopropane-1,1-dicarboxamidehydrochloride,N-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(S)-1-(4-fluorophenyl)propyl)cyclopropane-1,1-dicarboxamidehydrochloride,N-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(thiophen-2-yl)cyclopropane-1,1-dicarboxamide,N-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-((R)-1-(4-fluorophenyl)-2-methoxyethyl)cyclopropane-1,1-dicarboxamide,N-(4-fluorophenyl)-N-(4-(2-(4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yloxy)phenyl)cyclopropane-1,1-dicarboxamide,N-(4-fluorophenyl)-N′-(6-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)pyridin-3-yl)cyclopropane-1,1-dicarboxamide,2-(4-fluorophenyl)-N-(4-(2-(4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yloxy)phenylcarbamoyl)acetamide,N-(2,5-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,N-(4-fluorophenyl)-N′-(5-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)pyridin-2-yl)cyclopropane-1,1-dicarboxamide,N-(2,5-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenylcarbamoyl)-2-(4-fluorophenyl)acetamide,N-(2,3-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenylcarbamoyl)-2-(4-fluorophenyl)acetamide,2-(4-fluorophenyl)-N-(5-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)pyridin-2-ylcarbamoyl)acetamide,N-(2,5-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N-phenylcyclopropane-1,1-dicarboxamide,N-(5-chloro-2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenylcarbamoyl)-2-(4-fluorophenyl)acetamide,N-(5-chloro-2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,N-(3,5-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenylcarbamoyl)-2-(4-fluorophenyl)acetamide,N-(4-(2-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,N-(4-fluorophenyl)-N-(4-(2-(4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yloxy)phenyl)cyclopropane-1,1-dicarboxamide,N-(2-fluoro-5-methyl-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,N-(2-fluoro-4-methyl-5-(4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,N-(2-fluoro-5-(4-(1-methyl-1,4-pyrazol-4-yl)pyrimidin-2-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,N-(5-(4-(1H-pyrazol-4-yl)pyrimidin-2-yloxy)-2-fluoro-4-methylphenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,N-(5-(4-(1H-pyrazol-4-yl)pyrimidin-2-yloxy)-2-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,2-(4-fluorophenyl)-N-(4-methyl-5-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)pyridin-2-ylcarbamoyl)acetamide,N-(2,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,N-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)-N-methylcyclopropane-1,1-dicarboxamide,N-(2-fluoro-4-(2-(3-methylisoxazol-5-yl)pyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,andN-(4-(2-(1H-1,2,3-triazol-4-yl)pyridin-4-yloxy)-2-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.

1.11 Methods 1.11a Methods of Protein Modulation

The invention includes methods of modulating kinase activity of avariety of kinases, e.g. VEGFR-2 (KDR) kinase, c-MET kinase, FLT-3kinase, c-KIT kinase, PDGFR-α kinase, PDGFR-β kinase, and c-FMS kinase.The kinases may be wildtype kinases, oncogenic forms thereof, aberrantfusion proteins thereof or polymorphs of any of the foregoing. Themethod comprises the step of contacting the kinase species withcompounds of the invention and especially those set forth in section 1.The kinase species may be activated or unactivated, and the species maybe modulated by phosphorylations, sulfation, fatty acid acylationsglycosylations, nitrosylation, cystinylation (i.e. proximal cysteineresidues in the kinase react with each other to form a disulfide bond)or oxidation. The kinase activity may be selected from the groupconsisting of catalysis of phospho transfer reactions, inhibition ofphosphorylation, oxidation or nitrosylation of said kinase by anotherenzyme, enhancement of dephosphorylation, reduction or denitrosylationof said kinase by another enzyme, kinase cellular localization, andrecruitment of other proteins into signaling complexes throughmodulation of kinase conformation.

1.11b Treatment Methods

The methods of the invention also include treating individuals sufferingfrom a condition selected from the group consisting of cancer,hyperproliferative diseases, metabolic diseases, neurodegenerativediseases or diseases characterized by angiogenesis. These methodscomprise administering to such individuals compounds of the invention,and especially those of section 1, said diseases including, but notlimited to, solid tumors, malignant melanomas, glioblastomas, ovariancancer, pancreatic cancer, prostate cancer, lung cancers, breastcancers, kidney cancers, hepatic cancers, cervical carcinomas,metastasis of primary tumor sites, myeloproliferative diseases, chronicmyelogenous leukemia, leukemias, papillary thyroid carcinoma, non-smallcell lung cancer, mesothelioma, hypereosinophilic syndrome,gastrointestinal stromal tumors, colonic cancers, ocular diseasescharacterized by hyperproliferation leading to blindness includingvarious retinopathies, diabetic retinopathy and age-related maculardegeneration and hyperosinophilic syndrome, rheumatoid arthritis,asthma, chronic obstructive pulmonary disorder, mastocytosis, mast cellleukemia, a disease caused by PDGFR-α kinase, a disease caused byPDGFR-β kinase, a disease caused by c-KIT kinase, a disease caused bycFMS kinase, a disease caused by c-MET kinase and oncogenic forms,aberrant fusion proteins and polymorphs thereof. The administrationmethod is not critical, and may be from the group consisting of oral,parenteral, inhalation, and subcutaneous.

1.12 Pharmaceutical Preparations

The compounds of the invention, especially those of Section 1 may form apart of a pharmaceutical composition by combining one or more suchcompounds with a pharamaceutically acceptable carrier. Additionally, thecompositions may include an additive selected from the group consistingof adjuvants, excipients, diluents, and stablilizers.

SECTION 2 Synthesis of Compounds of the Present Invention

The compounds of the invention are available by the general syntheticmethods illustrated in the Schemes below and the accompanying examples.

In one aspect of the invention, compounds of general formula Ia containan aminergic “W” group and a cyclopropyl “V” group, and are representedby general formula 1. Compounds of general formula 1 can be readilyprepared by the union of amines of general formula 3, amines of generalformula 4 (t=0-3), and a cyclopropane dicarboxylic acid of formula 2. Asindicated below in Scheme 1, compounds of formula 1 can arise from thesequence 2→5→1 or alternately from the sequence 2→6→1. It will berecognized by those skilled in the art that the reaction arrows inScheme 1 represent either a single reaction or a multi-step reactionsequence. Bis-acid 2 can be coupled in a step-wise manner with amines 3and 4 through the use of standard peptide coupling agents known to thoseskilled in the art. Alternately, it will be understood in Scheme 1 thatacid 2 may be joined with amines 3 or 4 by pre-activation of one or bothcarboxylic acid moieties as an activated acid halide, anhydride, mixedanhydride or an activated ester (such as a pentafluorophenyl ester or ap-nitrophenyl ester). Such activated intermediates (not shown) may ormay not be isolated prior to reaction with amines 3 or 4. Those skilledin the art will further recognize that the carboxylic acid moieties of 2may enter the reaction Scheme 1 masked as esters and the reactionsequences in Scheme 1 allow for additional de-protection steps, ifnecessary, to convert an ester derivative of 5, or 6 into acids 5 or 6to facilitate the formation of the second amide bond.

Non-limiting examples of Scheme 1 are shown in Schemes 2-4. Scheme 2illustrates the preparation of compound 11, an example of generalformula 1 (wherein A is 4-fluorophenyl, t is 0, Z2B is 11, Q3 is CH, theQ3 ring is substituted with fluorine, and the D-containing ring ispyrazole) by the general sequence of 2→5→1 (Scheme 1). Thus, asindicated below, the union of 1,1-cyclopropane bis-carboxylic acid (7,an example of general intermediate 2, vide supra), with amine 8 (anexample of general amine 3) provides the amide/acid 9, an example ofgeneral intermediate 5. Conditions for the transformation include the insitu activation of bis-acid 7 by treatment with thionyl chloride in thepresence of a tertiary base, such as triethylamine, followed by reactionwith amine 8. Further reaction of 9 with amine 10 (an example of generalintermediate 4) in the presence of a peptide coupling agent providesbis-amide 11. Coupling agents for the later transformation include TBTU(0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate),PyBOP (benzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate), EDC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride) and BOP-Cl(bis(2-oxo-3-oxazolidinyl)phosphonic chloride).

Similarly, Scheme 3 illustrates an additional example of the generalsequence of 2→5→1 (Scheme 1) commencing with the mono-ester 12. Thus,acid/ester 12 is combined amine 13 to provide ester/amide 14.Saponification of the ester of 14 with lithium hydroxide provides thelithium carboxylate 15. Treatment of 15 with 10 and a peptide couplingreagent, for example TBTU, provides bis-amide 16, a further example ofgeneral formula 1

Scheme 4 illustrates the preparation of 19 as a non-limiting example ofthe general sequence 2→6→1 of Scheme 1. Thus, bis-acid 7 is firstcoupled with amine 10 to provide the amide/acid 17, which is in turncoupled with amine 18 to provide 19.

In another aspect of the invention, the “V” moiety of formula Ia is NR4.In these instances, compounds of formula 20 can be prepared as indicatedin Scheme 5 by the reaction of general amine 3 with general intermediate21, or, in the instance when R4 is H, with isocyanate 22.

General intermediate 21 is available from 23 by reaction with phosgeneor a phosgene surrogate such as diphosgene or triphosgene, as indicatedin Scheme 6. Non-commercially-available isocyanates 22 can be preparedby the treatment of general acid chloride 24 with silver isocyanate.Acid chlorides 24 in turn are prepared from the corresponding acids byconditions familiar to those skilled in the art. Alternately, 22 can beprepared from amide 25 by treatment with oxalyl chloride or phosgene,optionally with heating.

A non-limiting example of Schemes 5 and 6 is illustrated by thepreparation of 29 in Scheme 7. Thus, acid 26 (see: Jiang, Y., et al., J.Med. Chem. (2007) 50(16): 3870) is converted to acid chloride 27 upontreatment with oxalyl chloride in toluene containing a catalytic amountof dimethylformamide. Further treatment of 27 with silver isocyanateprovides isocyanate 28, an example of general intermediate 22 (Scheme6). Finally, reaction of 28 with amine 18 provides N-acyl urea 29, anexample of general formula 20 (wherein A is 4-fluorophenyl, W is—CH(CH₃)—, R4 is H, Q3 is CH, the Q3 ring is substituted with fluorine,Q2 is CH, Q1 is N, and the D-containing ring is pyrazole).

An additional example illustrating the general methods of Schemes 5 and6 is the synthesis of 33 shown in Scheme 8. Thus,4-fluorophenylacetamide 30, readily prepared from 4-fluorophenylaceticacid and ammonia, is first treated with oxalyl chloride with heating toprovide 2-(4-fluorophenyl)acetyl isocyanate 31. Further treatment ofisocyanate 31 with amine 32 provides the N-acyl urea 33, an example ofgeneral intermediate 20 (wherein A is 4-fluorophenyl, W is —CH₂—, R4 isH, Q3 is N, Q2 is CH, Q1 is N, and the D-containing ring is pyrazole).

Amines 3 useful for the invention can be synthesized according tomethods commonly known to those skilled in the art. One generalpreparation of amines of formula 3 involves the stepwise union of threemonocyclic subunits by formation of a C—O bond between the Q1/Q2 and Q3rings and the formation of a bond between the Q1/Q2 ring and the5-membered D-ring. Variations of this method are shown in the followingschemes.

Scheme 9 illustrates one general mode of assembly of 3 in which theether oxygen atom of 3 is derived from a hydroxyl moiety on theQ3-containing subunit 34. The union of fragment 34 with theQ1/Q2-containing ring 35 is accomplished by treatment of 34 with a base,for example potassium tert-butoxide, and fragment 35 with optionalheating to form the ether 36. In Scheme 9, the “LG” of monocycle 35represents a moiety that can be directly displaced in a nucleophilicsubstitution reaction (with or without additional activation), forexample a halide, sulfonate, sulfone or sulfoxide. The “X” group ofmonocycle 35 or bicycle 36 represents a moiety that allows theattachment of a 5-membered heterocyclic moiety. In one aspect, the “X”group represents a halogen atom that will participate in atransition-metal-mediated coupling with a pre-formed heterocyclic(D-ring) reagent (for example a boronic acid or ester, or heteroarylstannane) to give rise to amine 3. In another aspect, the “X” grouprepresents a leaving group to be displaced by a nitrogen atom of apyrazole, imidazole or triazole to install the D-ring. In anotheraspect, the X group represents a moiety through which to construct the5-membered D-ring (pyrazole, isoxazole, triazole, imidazole), forexample a carboxylic acid or ester, alkyne, or aldehyde that can betransformed into a 5-membered ring.

Some non-limiting examples of general Scheme 9 are illustrated in theSchemes below. Scheme 10 illustrates the preparation of pyrazole 8, anexample of general amine 3 (wherein R4 is E1, Q3 is CH, the Q3 ring issubstituted with fluorine, Q2 is CH, Q1 is N, and the D-containing ringis pyrazole). In Scheme 10, commercially available3-fluoro-4-aminophenol (37) is reacted with potassium tert-butoxide and2,4-dichloropyridine 38 (an example of 35 wherein LG and X are bothchloro) to provide chloropyridine 39, an example of general intermediate36. Possible conditions for this transformation are dimethylacetamide ata temperature between 80 and 100° C. The subsequent reaction ofchloropyridine 39 with the commercially available pyrazole-4-boronicacid pinacol ester 40 in the presence of a palladium catalyst, forexample tetrakis(triphenylphosphine) palladium(0), provides pyrazoleamine 8.

Scheme 11 illustrates the preparation of additional non-limitingexamples of amine 3 using the general methods of Scheme 9 and Scheme 10.Thus, general intermediate 36 (X=halogen) can be converted to compounds46-50 using a palladium-catalyzed cross coupling with reagents 41(Milestone PharmTech), 42 (Alfa), 43 (see: Nicolaou, et. al., Chem MedChem, (2006), 1(1): 41), 44 (Frontier Scientific), 45 (see: Sakamoto, etal. Tetrahedron, (1991), 47(28): 5111), respectively. Suitable palladiumcatalysts for the reactions of Scheme 11 includedichlorobis(triphenylphosphine)palladium,dichloro[11′-bis(diphenylphosphino) ferrocene]palladium andtetrakis(triphenylphosphine) palladium.

Additional heteroaryl boronates and stannanes useful for the inventioncan be prepared form the corresponding heteroaryl halides. For example,the known triazole bromides 51-53 (See: Pedersen, C. Acta Chem. Scand.(1959) δ: 888-892) in Scheme 12 can be converted to the correspondingtributylstannanes 54-56. Suitable conditions for this transformationinclude reaction with hexabutyldistannane andpalladiumtetrakis(triphenylphosphine) at elevated temperatures, forexample between 60 and 180° C. Alternative conditions for thetransformation include treatment of the bromides 51-53 withn-butyllithium at low temperature and subsequent treatment of theresultant organolithium intermediates with tributyltin chloride.Stannanes 54-56 in turn can undergo reaction with general halide 36 inthe presence of a palladium catalyst to form triazole-containing amines57-59, examples of general amine 3.

Schemes 13-16 illustrate the preparation of non-limiting examplesgeneral amine 3 wherein the D-ring is a pyrazole, imidazole or triazolering linked to the Q1/Q2 ring through a nitrogen atom. Schemes 13-16 areexamples of general Scheme 9 wherein the “X” group of 36 is a leavinggroup for nucleophilic aromatic substitution. Suitable X groups forSchemes 13-16 include halogen, including chlorine. Suitable conditionsfor Schemes 13-16 include the use of polar aprotic solvents such as1-methyl-2-pyrrolidinone, dimethylacetamide, or dimethylsulfoxide in thepresence of non-nucleophilic bases such as potassium carbonate, sodiumhydride, 1,8-diaza-bicyclo[5.4.0]undec-7-ene (DBU), and the like.Possible temperatures are from ambient temperature up to about 250° C.and may optionally include the use of microwave irradiation orsonication.

Scheme 13 illustrates the reaction of general intermediate 36 withpyrazole 60 (example commercially available pyrazoles include those withR20=H, CH₃, CN, and CF₃), or pyrazole 61 (example commercially availablepyrazoles include those with R20=CH₃, and CF₃) to provide pyrazoles 62,63 or 64, non-limiting examples of general amine 3 wherein the D-ring ispyrazole.

Similarly, Scheme 14 illustrates the reaction of general intermediate 36with imidazole 65 (example commercially available imidazoles includethose with R20=H, CH₃, CN, CF₃, and 2-hydroxyethyl) to provide 66 and67, non-limiting examples of general amine 3 wherein the D-ring isimidazole.

Scheme 15 illustrates the reaction of general intermediate 36 withtriazole 68 (example commercially available triazoles include those withR20=H, CH₃, and CN) to provide 69, 70, and 71, non-limiting examples ofgeneral amine 3 wherein the D-ring is a 1,2,4-triazole.

Scheme 16 illustrates the reaction of general intermediate 36 withtriazole 72 (example commercially available triazoles include those withR20=H, hydroxymethyl) to provide 73, 74, and 75, non-limiting examplesof general amine 3 wherein the D-ring is a 1,2,3-triazole.

Scheme 17 illustrates the preparation of amines 78 and 79, non-limitingexamples of general amines 3, as an example of Scheme 9 wherein anannulation sequence is employed to construct a triazole ring (D-ring).Thus, conversion of chloropyridine 39 into alkyne 76 is accomplished bySonogashira cross-coupling with trimethylsilylacetylene, followed byremoval of the trimethylsilyl group by conditions familiar to thoseskilled in the art, for example K₂CO₃ in methanol. Further reaction ofalkyne 76 with azidomethyl pivalate (77) in the presence of coppersulfate and sodium ascorbate provides the N-pivaloylymethyl triazoleamine 78 (see Loren, et. al. Synlett, (2005), 18: 2847). The pivalate 78is a masked equivalent of NH-triazole 79. Removal of the pivalate moietywith NaOH provides 79. Alternately, 78 can be used directly in generalSchemes 1 or 5 to provide compound of Formula 1 or 20 wherein the D-ringtriazole is masked with the pivaloylymethyl group. Further treatment ofsuch product with NaOH provides NH-triazoles of Formula 1 or 20.

As an extension of Scheme 17, Z3-substituted triazoles of formula 81 and

R20-substituted isoxazole of formula 83 can also be prepared byanalogous 1,3-dipolar cycloadditions as shown in Scheme 18. Thus,combination of Z3-substituted azides 80, readily prepared fromcommercial alkyl halides and sodium azide, with alkyne 76, sodiumascorbate, and Cu(SO₄) pentahydrate (See: Rostotsev, et. al. Angew.Chem. Int. Ed, (2002) 41 (14): 2596-2599) gives rise to Z3-substitutedtriazoles 81. In a similar sequence, the combination of R20-substitutedoximes 82, readily prepared from aldehydes and hydroxylamine, withN-chlorosuccinimide in the presence of alkyne 76 with heating, oroptional microwave irradiation, provides isoxazoles of formula 83,additional examples of general amine 3.

An additional example of Scheme 9 wherein an annulation sequence isemployed to construct an imidazole D-ring is shown in Scheme 19 for thesynthesis of imidazole 93, an example of general amine 3 (wherein R4 isH, Q3 is CH, Q2 is CH, Q1 is N, and the D-containing ring is substitutedimidazole (R20=CF₃)). Conversion of pyridine-2-carboxylic acid (84) tochloro-pyridine 85 is accomplished by treatment with thionyl chlorideand sodium bromide with heating. Reaction of 85 with tert-butanolprovides the chloro-ester 86, an example of general intermediate 35(Scheme 9, wherein LG is chloro and X is tert-butoxycarbonyl). Treatmentof 86 with the sodium salt of 4-aminophenol 87, prepared from 87 withsodium hydride, and heating the resultant mixture to 80° C. providesether-ester 88, an example of general intermediate 36 (Scheme 9, whereinX is tert-butoxycarbonyl). The further conversion of 88 to 93illustrates the potential multi-step nature of the second reaction arrowof general Scheme 9. Thus, treatment of 88 with di-tert-butyldicarbonate provides the Boc-protected intermediate 89. Reduction of theester moiety of 89 with LiAlH₄ provides the alcohol 90, which in turn isoxidized with MnO₂ to provide aldehyde 91, a further example of generalintermediate 36 (wherein X is formyl). Further reaction of 91 with3,3-dibromo-1,1,1-trifluoro-propan-2-one, sodium acetate, and ammoniumhydroxide provides the imidazole 92. Removal of the Boc group of 92using aqueous HCl provides 93, an example of general amine 3.

Scheme 20 illustrates the general preparation of additional pyrazole andisoxazole isomers by an annulation sequence. Thus, aldehyde 91, arepresentative example of general intermediate 36 (wherein R4 is a Bocprotecting group, Q3 is H, Q2 is H, Q1 is N and X is formyl), isconverted to ketone 94 by sequential treatment with methyl magnesiumbromide followed by oxidation using standard conditions familiar tothose skilled in the art. Subsequent treatment of 94 with thedimethylacetal of dimethylormamide affords 95. Further treatment of 95with Z3-substituted hydrazine 96 provides a mixture of 97 and 99containing an N-Boc protecting group. Removal of the Boc protectinggroup under standard acidic conditions provides 98 and 100, examples ofgeneral amine 3 wherein the D-ring is Z3-substituted pyrazole. In asimilar fashion, treatment of intermediate 95 with hydroxylamineprovides isoxazoles 101 and 103 containing an N-Boc protecting group.Removal of the Boc protecting group under standard acidic conditionsprovides 102 and 104, examples of general amine 3 wherein the D-ring isisoxazole.

In a similar manner, Scheme 21 illustrates the preparation ofR20-substituted pyrazole and isoxazole rings. Thus, ketone 94, arepresentative example of general intermediate 36 (wherein R4 is a Bocprotecting group, Q3 is H, Q2 is H, Q1 is N and X is acetyl), isconverted to di-ketone 105 by sequential treatment with a strong baseand an R20-substituted acylation reagent, for example an acid halide orester. Further treatment of 105 with Z3-substituted hydrazine 96provides a mixture of 106 and 107 containing an N-Boc protecting group.Removal of the Boc protecting group under standard acidic conditionsprovides 108 and 109, examples of general amine 3 wherein the D-ring isan R20- and Z3-substituted pyrazole. In a similar fashion, treatment ofintermediate 105 with hydroxylamine provides isoxazoles 110 and 111containing an N-Boc protecting group. Removal of the Boc protectinggroup under standard acidic conditions provides 112 and 113, examples ofgeneral amine 3 wherein the D-ring is an R20-substituted isoxazole.

Scheme 22 illustrates another general mode of assembly of 3 in which theether oxygen atom of 3 is derived from a hydroxyl moiety on theQ1/Q2-containing subunit 115. The union of intermediate 114 with theQ1/Q2-containing ring 115 is accomplished by treatment of 115 with abase, for example potassium tert-butoxide, and fragment 114 withoptional heating to form the ether 116. In Scheme 22, the “LG” ofmonocycle 114 represents a moiety that can be directly displaced in anucleophilic substitution reaction (with or without additionalactivation), for example a halide, sulfonate, sulfone, sulfoxide ornitro. The “X” group of monocycle 115 or bicycle 116 represents a moietythat allows the attachment of a 5-membered heterocyclic moiety. In oneaspect, the “X” group represents a halogen atom that will participate ina transition-metal-mediated coupling with a pre-formed heterocyclic(D-ring) reagent (for example a boronic acid or ester, or heteroarylstannane) to give rise to amine 118. In another aspect, the “X” grouprepresents a leaving group to be displaced by a nitrogen atom of apyrazole, imidazole or triazole to install the D-ring. In anotheraspect, the X group represents a moiety through which to construct the5-membered D-ring (pyrazole, isoxazole, triazole, imidazole), forexample a carboxylic acid or ester, alkyne, or aldehyde, that can betransformed into a 5-membered ring-containing intermediate 118.Subsequent to the formation of nitro ether 116, the nitro moiety isconverted to an amino moiety by subjecting 116 to reducing conditionsknown to those skilled in the art, for example iron powder, zinc powder,indium powder, stannous chloride, or hydrogenation in the presence of ametallic catalyst, for example a nickel or palladium catalyst whichaffords amine 117. Conversion of the “X” group-containing intermediate117 to the 5-membered D-ring-containing intermediate 118 is thusaccomplished by the methods described in the schemes above to provide118, an example of general amine 3 wherein R4 is H. If desired, amine118 can be alkylated with an R4 moiety by standard conditions to providegeneral amine 3.

A non-limiting example of Scheme 22 is shown below for the preparationof 32 (Scheme 23), an example of general amine 118 (wherein Q3 is N, Q2is CH, Q1 is N, and the D-containing ring is pyrazole). In Scheme 23,commercially available 5-bromo-2-nitropyridine (119) is reacted with2-chloro-4-hydroxypyridine (120) and a base, for example cesiumcarbonate, at elevated temp, for example 80° C., to afford nitropyridine121, an example of general intermediate 116. Possible conditions forthis transformation are dimethylformamide at a temperature between 80and 100° C. Further reaction of nitropyridine 121 with zinc dust in thepresence of ammonium chloride provides aminopyridine 122. Furtherreaction of 122 with pyrazole-4-boronic acid pinacol ester 40 by theconditions described previously provide the pyrazole amine 32, anexample of general amine 118.

Scheme 24 illustrates another general method of preparing amines 3 byfirst attaching the 5-membered heterocycle to the Q1/Q2 ring (35). Asdescribed for Scheme 9, the “LG” of monocycle 35 represents a moietythat can be directly displaced in a nucleophilic substitution reaction(with or without additional activation). The “X” group of monocycle 35represents a moiety that allows the attachment of a 5-memberedheterocycle. In one aspect, the “X” group represents a halogen atom thatwill participate in a transition-metal-mediated coupling with apre-formed heterocyclic reagent (for example, a boronic acid or ester,or heteroaryl stannane) to give rise to amine 3. In another aspect, the“X” group of 35 represents a functional group that can be converted to afive-membered heterocycle by an annulation reaction. Additionally, the“X” group of 35 may represent a leaving group (halogen, sulfoxide,sulfone, sulfonate) that can be displaced by a nucleophilic nitrogenatom of a pyrazole, triazole or imidazole ring. After conversion of 35to 123, the “LG” moiety can be displaced by a hydroxyl group on theQ3-containing ring to provide the tricyclic ether-amine 3. Those skilledin the art will recognize that each reaction arrow in Scheme 24 mayrepresent a single transformation or a series of transformations.

A specific, non-limiting example of Scheme 24 is illustrated in Scheme25 by the preparation of amine 128, an example of general amine 3(wherein Q3 is CH and the Q3 ring is substituted with fluoro, Q2 is N,Q1 is N, and the D-containing ring is pyrazole). Thus, commerciallyavailable pyrimidine 124, an example of general intermediate 35,undergoes a palladium-catalyzed coupling with the commercially availablepyrazole boronate 40 to provide the bicycle 125, an example of generalintermediate 123 (Scheme 24). Oxidation of the sulfide moiety of 125(The “LG” group of general intermediate 123) with m-chloroperbenzoicacid further activates this moiety toward nucleophilic displacement andgives rise to intermediate 126. Treatment of sulfone 126 with phenol 127in the presence of a base provides tricyclic amine 128, an example ofgeneral amine 3. Possible bases for the later transformation includepotassium carbonate and potassium tert-butoxide in polar aproticsolvents such as dimethylformamide or dimethylacetamide.

An additional non-limiting example of general Scheme 24 is illustratedin Scheme 26 by the preparation of 131, an additional example of generalamine 3 (wherein Q3 is CH and the Q3 ring is substituted with fluoro, Q2is N, Q1 is N, and the D-containing ring is pyrazole). Thus,commercially available dichloropyrimidine 129, an example of generalintermediate 35 wherein both “LG” and “X” are chloro, undergoes apalladium-catalyzed coupling with the commercially available pyrazoleboronate 40 to provide the bicycle 130, an example of generalintermediate 123 (Scheme 24). Addition of phenol 37 in the presence of abase at elevated temperature then provides amine 131.

Scheme 27 illustrates the preparation amine 134 as an additionalnon-limiting example of general Scheme 9. Thus, by direct analogy toScheme 10, 2,4-dichloropyrimidine (132) can be reacted with phenol 37 inthe presence of a base to provide 133, an example of generalintermediate 36 (Scheme 9). Further reaction of chloropyrimidine 133with pyrazole boronate 40 in the presence of palladium catalyst providesamine 134, an example of general amine 3.

Additional preferred synthetic methods for the preparation of compoundsof formula 1 are found in the following examples.

SECTION 3 Examples

The disclosure is further illustrated by the following examples, whichare not to be construed as limiting this disclosure in scope or spiritto the specific procedures herein described. It is to be understood thatthe examples are provided to illustrate certain embodiments and that nolimitation to the scope of the disclosure is intended thereby. It is tobe further understood that resort may be had to various otherembodiments, modifications, and equivalents thereof which may suggestthemselves to those skilled in the art without departing from the spiritof the present disclosure and/or scope of the appended claims.

Example A1

A suspension of 3-fluoro-4-aminophenol (8.0 g, 63.0 mmol) indimethylacetamide (80 mL) was de-gassed in vacuo and treated withpotassium tert-butoxide (7.3 g, 65 mmol). The resultant mixture wasstirred at RT for 30 min. 2,4-Dichloropyridine (8 g, 54 mmol) was addedand the mixture was heated to 80° C. for 12 h. The solvent was removedunder reduced pressure to give a residue which was partitioned betweenwater and EtOAc (3×100 mL). The organic layers were washed withsaturated brine, dried (MgSO₄), concentrated in vacuo and purified bysilica gel column chromatography to give4-(2-chloropyridin-4-yloxy)-2-fluorobenzenamine (11 g, 86% yield). ¹HNMR (300 MHz, DMSO-d6): δ 8.24 (d, J=5.7 Hz, 1H), 7.00 (dd, J=9.0, 2.7Hz, 1H), 6.89-6.73 (m, 4H), 5.21 (br s, 2H); MS (ESI) m/z: 239.2 (M+H+).

A solution of 4-(2-chloropyridin-4-yloxy)-2-fluorobenzenamine (3 g, 12.6mmol),1-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole(5.2 g, 25.2 mmol), and Na₂CO₃ (2.7 g, 25.2 mmol) in DME (18 mL)/water(6 mL) was sparged with nitrogen for 20 min. Pd(PPh₃)₄ (729 mg, 0.63mmol) was added and the resulting mixture was heated to 100° C. for 16h. The solvent was removed under reduced pressure and the crude productwas suspended in water and extracted with EtOAc. The organic layer waswashed with brine, dried (Na₂SO₄), concentrated in vacuo. and purifiedvia silica gel chromatography to give2-fluoro-4-(2-(1-methyl-1,4-pyrazol-4-yl)pyridin-4-yloxy)benzenamine (2g, 56% yield). ¹H NMR (300 MHz, DMSO-d₆): δ 8.31 (d, J=5.7 Hz, 1H), 8.21(s, 1H), 7.92 (s, 1H), 7.12 (d, J=2.4 Hz, 1H), 6.96 (m, 1H), 6.85-6.72(m, 2H), 6.56 (m, 1H), 5.15 (s, 2H), 3.84 (s, 3H); MS (ESI) m/z: 285.0(M+H⁺).

Example A2

Using a procedure analogous to Example A1, 2-fluoro-4-aminophenol (2.6g, 24 mmol) and 2,4-dichloropyridine (2.88 g, 20 mol) were combined toprovide 4-(2-chloropyridin-4-yloxy)-3-fluoroaniline (3.2 g, 67% yield).¹H NMR (400 MHz, DMSO-d₆): δ 8.25 (d, J=5.6 Hz, 1H), 6.99 (m, 1H), 6.90(m, 2H), 6.50 (d, J=1.6 Hz, 1H), 6.41 (d, J=10.4 Hz, 1H), 5.51 (s, 2H);MS (ESI) m/z: 239.1 (M+H⁺).

Using a procedure analogous to Example A1,4-(2-chloropyridin-4-yloxy)-3-fluoroaniline (3 g, 11.6 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(3.4 g, 16.4 mmol), Na₂CO₃ (2.7 g, 25.2 mmol) and Pd(Ph₃)₄ (1.5 g, 0.1eq) were combined to give3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)aniline (1.1 g,34% yield). ¹H NMR (400 MHz, DMSO-d₆): δ (8.31 (d, J=5.6 Hz, 1H), 8.22(s, 1H), 7.93 (s, 1H), 7.14 (s, 1H), 6.98 (m, 1H), 6.55-6.49 (m, 2H),6.42 (d, J=7.2 Hz, 1H), 5.44 (s, 2H), 3.86 (s, 3H); MS (ESI) m/z:(M+H⁺): 285.2.

Example A3

1,2,3-Trifluoro-4-nitrobenzene (30 g, 0.17 mol), benzyl alcohol (18.4 g,0.17 mol) and K₂CO₃ (35 g, 0.25 mol) were combined in DMF (300 mL) andwere stirred at RT for 8 h. Water (300 mL) was added, and the mixturewas extracted with EtOAc (3×500 mL). The combined organic layers werewashed with brine, dried (MgSO₄), concentrated in vacuo and purified bycolumn chromatography on silica gel to give1-benzyloxy-2,3-difluoro-4-nitrobenzene (16 g, 36% yield). ¹H NMR (400MHz, DMSO-d₆): δ 8.06 (m, 1H), 7.49-7.30 (m, 6H), 5.37 (s, 2H).

A solution of 1-benzyloxy-2,3-difluoro-4-nitrobenzene (14 g, 52.8 mmol)in MeOH (200 mL) was stirred with Pd/C (10%, 1.4 g, 1.3 mmol) under ahydrogen atmosphere (30 psi) for 2 h. The catalyst was removed byfiltration, and the filtrate was concentrated in vacuo to afford4-amino-2,3-difluorophenol (7 g, 92% yield). ¹H NMR (400 MHz, DMSO-d₆):δ 9.05 (s, 1H), 6.45 (t, J=8.8 Hz, 1H), 6.34 (t, J=9.2 Hz, 1H), 4.67 (s,2H); MS (ESI) m/z: 146.1 [M+H]⁺.

4-amino-2,3-difluorophenol (6 g, 41.4 mmol) and potassium tert-butoxide(4.9 g, 43.5 mmol) were suspended in DMAc (200 mL) and stirred at RT for30 min under Ar atmosphere. 2,4-Dichloropyridine (6.1 g, 41.4 mmol) wasadded, and the resulting mixture was heated to 70° C. for 8 h. Thereaction mixture was filtered, concentrated in vacuo and purified bysilica gel chromatography to afford4-(2-chloro-pyridin-4-yloxy)-2,3-difluoro-phenylamine (7 g, 66% yield).¹H NMR (400 MHz, DMSO-d₆): δ 8.27 (d, =6.0 Hz, 1H), 7.05 (s, 1H), 6.95(m, 1H), 6.92 (m, 1H), 6.62 (m, 1H), 5.60 (s, 2H); MS (ESI) m/z: 257.1[M+H]⁺.

Nitrogen was bubbled though a solution of4-(2-chloro-pyridin-4-yloxy)-2,3-difluoro-phenylamine (2 g, 7.8 mmol),1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole(1.6 g, 7.8 mmol) and Na₂CO₃ (1.65 g, 15.6 mmol) in DME (12 mL)/H₂O (4mL) for 20 min. Pd(PPh₃)₄ (450 mg, 0.4 mmol), was added and thenresulting mixture was degassed in vacuo, blanketed with nitrogen andheated to 70° C. for 16 h. The reaction was concentrated to drynessunder reduced pressure. The crude product was suspended in water andextracted with EtOAc (3×10 mL). The organic layer was washed with brine,dried (Na₂SO₄), concentrated in vacuo and purified by silica gelchromatography to give2,3-difluoro-4-[2-(1-methyl-1H-pyrazol-4-yl)-pyridin-4-yloxy]-phenylamine(1.3 g, 55% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.40 (d, J=6.0 Hz, 1H),8.32 (s, 1H), 8.02 (s, 1H), 7.26 (s, 1H), 6.96 (t, J=8.8 Hz, 1H),6.71-6.68 (m, 2H), 5.62 (s, 2H), 3.92 (s, 3H); MS (ESI) m/z: 303.2[M+14]⁺.

Example A4

A solution of 4-amino-2-methyl-phenol (4.25 g, 34.5 mmol) indimethylacetamide (50 mL) was degassed in vacuo and blanketed withargon. Potassium tert-butoxide (5.0 g, 44.6 mmol) was added and thereaction mixture was de-gassed a second time and stirred at RT underargon for 30 min. 2,4-Dichloro-pyridine (4.6 g, 31.3 mmol) was added andthe mixture was heated to 100° C. overnight. The solvent was removedunder reduced pressure and the residue was purified by silica gelchromatography to give 4-(2-chloropyridin-4-yloxy)-3-methylbenzenamine(4.5 g, 56% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.21 (d, J=5.2 Hz, 1H),6.75-6.80 (m, 3H), 6.45-6.50 (m, 2H), 5.15 (s, 2H), 1.92 (s, 3H); MS(ESI) m/z: 235.1 (M+H⁺).

A solution of 4-(2-chloropyridin-4-yloxy)-3-methylbenzenamine (595 mg,2.54 mmol),1-methyl-4-(4,4,5,5-tetramethyl)-[1,3,2]dioxaborolan-2-yl)-4H-pyrazole(790 mg, 3.80 mmol) and Cs₂CO₃ (2.53 g, 7.77 mmol) in 10 mL of DMF (10mL)/water (3 mL) was de-gassed under vacuum and blanketed with nitrogen.Pd(PPh₃)₄ (295 mg, 0.26 mmol) was added and the reaction mixture washeated to 90° C. overnight. The reaction mixture was diluted with EtOAc(30 mL) and washed with water (2×10 mL) and brine (2×10 mL). The aqueousportion was extracted with EtOAc (2×15 mL) and the combined organicswere washed with brine (10 mL), concentrated in vacuo and purified onsilica gel to provide3-methyl-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)benzenamine as apale yellow foam (627 mg, 88% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.27(d, J=6.0 Hz, 1H), 8.18 (s, 1H), 7.90 (d, J=0.7 Hz, 1H), 7.07 (d, J=2.2Hz, 1H), 6.74 (d, J=8.6 Hz, 1H), 6.49 (d, J=2.5 Hz, 1H), 6.46-6.40 (m,2H), 5.02 (s, 2H), 3.84 (s, 3H), 1.94 (s, 3H); MS (ESI) m/z: 281.2(M+H⁺).

Example A5

KOtBu (1.016 g, 9.05 mmol) was added to a solution of4-amino-2-chlorophenol (1.00 g, 6.97 mmol) in DMF (35 ml) at RT and theresultant mixture was stirred 45 min. 2,4-Dichloropyridine (1.340 g,9.05 mmol) was then added and the reaction was stirred with heating at90° C. overnight. The reaction was cooled to RT and diluted generouslywith H₂O and EtOAc. The layers were separated. The aqueous was extractedwith EtOAc (3×). The combined organics were washed with H₂O (1×) andbrine (2×), dried (MgSO₄), concentrated in vacuo and purified by silicagel chromatography (EtOAc/hexanes) to afford3-chloro-4-(2-chloropyridin-4-yloxy)benzenamine (0.89 g, 50% yield) as awaxy yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.24 (d, J=5.7 Hz, 1H),7.02 (d, J=8.7 Hz, 1H), 6.87-6.82 (m, 2H), 6.73-6.72 (m, 1H), 6.58-6.56(m, 1H), 5.50 (br s, 2H); MS (ESI) m/z: 254.9 (M+H⁺); 256.9 (M+2+H⁺).

3-Chloro-4-(2-chloropyridin-4-yloxy)benzenamine (0.89 g, 3.49 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrazole (0.871g, 4.19 mmol) and K₂CO₃ (1.302 g, 9.42 mmol) were combined in DME (6ml)/H₂O (7.5 ml) and the headspace was flushed with Ar for 10 min.Pd(Ph₃P)₄ (0.202 g, 0.174 mmol) was then added and the biphasic reactionwas stirred with heating at 90° C. overnight. The reaction was cooled toRT and filtered to remove insoluble material. The filtrate was dilutedwith THF and washed with brine (3×). The combined aqueous phases wereextracted with THF (2×). The combined organics were washed with brine(1×), dried (MgSO₄), concentrated in vacuo and purified by silica gelchromatography (MeOH/CHCl₃) to afford3-chloro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)benzenamine(1.10 g, 83% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.30-8.29 (m, 1H),8.22 (s, 1H), 7.92 (s, 1H), 7.12 (m, 1H), 7.00-6.98 (m, 1H), 6.72 (br s,1H), 6.58-6.54 (m, 1H), 6.47-6.44 (m, 1H), 5.44 (s, 2H), 3.84 (s, 3H);MS (ESI) m/z: 301.1 (M+H⁺): 303.0 (M+2+H⁺).

Example A6

To a solution of 4-(2-chloropyridin-4-yloxy)-3-fluoroaniline (3.0 g,12.6 mmol, from Example A2) in a solvent comprised oftoluene/ethanol/water (4:4:1, 50 mL) was added4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (3.17 g,16.4 mmol), sodium carbonate (4.01 g, 37.8 mmol) andtetrakis(triphenylphosphine)palladium (0.73 g, 0.63 mmol). The headspacewas evacuated and back-filled with nitrogen (3×) and then the reactionmixture was heated to 100° C. overnight. The reaction was concentratedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (ethyl acetate/petroleum ether) to give4-(2-(1H-pyrazol-4-yl)pyridin-4-yloxy)-3-fluoroaniline (2.66 g, 78%yield). ¹H NMR (400 MHz, DMSO-d₆): δ 13.03 (brs, 1H), 8.28-8.31 (m, 2H),7.99 (s, 1H), 7.24 (s, 1H), 6.95-7.00 (m, 1H), 6.39-6.50 (m, 3H), 5.43(brs, 2H); MS (ESI): m/z 271.1 [M+H]⁺.

Example A7

A solution of 1,3-difluoro-2-methyl-benzene (15 g, 0.12 mol) in H₂SO₄(100 mL) was treated dropwise with 65% HNO₃ (11.4 g, 0.12 mol) at −10°C. and the resultant mixture was stirred for about 30 min. The mixturewas poured into ice-water and extracted with ethyl acetate (3×200 mL).The combined organic layers were washed with brine, dried (Na₂SO₄) andconcentrated in vacuo to give 1,3-difluoro-2-methyl-4-nitro-benzene (16g, 78% yield). ¹H NMR (400 MHz, CDCl₃): δ 7.80 (m, 1H), 6.95 (m, 1H),2.30 (s, 3H).

1,3-Difluoro-2-methyl-4-nitro-benzene (16 g, 0.092 mol), benzyl alcohol(10 g, 0.092 mol) and K₂CO₃ (25.3 g, 0.18 mol), were combined in DMF(300 mL) and heated to 100° C. overnight. The mixture was poured intowater and extracted with ethyl acetate (3×200 mL). The combined organiclayers were washed with brine, dried (Na₂SO₄), concentrated in vacuo andpurified by silica gel chromatography to give1-benzyloxy-3-fluoro-2-methyl-4-nitro-benzene (8 g, 33% yield). ¹H NMR(400 MHz, DMSO-d₆): δ 8.04 (t, J=8.8 Hz, 1H), 7.30-7.46 (m, 5H), 7.08(d, J=9.2 Hz, 1H), 5.28 (s, 2H), 2.13 (s, 3H).

Using a procedure analogous to Example A3,1-benzyloxy-3-fluoro-2-methyl-4-nitro-benzene (8 g, 0.031 mol) washydrogenated to give 4-amino-3-fluoro-2-methyl-phenol (4.2 g, 96%yield). ¹H NMR (300 MHz, DMSO-d₆): δ 8.61 (s, 1H), 6.36 (m, 2H), 4.28(s, 2H), 1.96 (s, 3H); MS (ESI) m/z: 142.1 [M+H]⁺.

Potassium tert-butoxide (3.5 g, 31 mmol) was added to a solution of4-amino-3-fluoro-2-methyl-phenol (4.2 g, 30 mmol) in dimethylacetamide.The mixture was stirred at RT for 30 min. A solution of2,4-dichloropyridine (4.38 g, 30 mmol) in dimethylacetamide was addedand the mixture was heated at 100° C. overnight. The reaction mixturewas concentrated in vacuo and the residue was dissolved in ethyl acetate(200 mL) and filtered through silica gel. The filter cake was washedwith ethyl acetate, the combined filtrates were concentrated in vacuoand purified by silica gel chromatography to give4-(2-chloro-pyridin-4-yloxy)-2-fluoro-3-methyl-phenylamine (3.2 g, 42%yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.21 (d, J=6.4 Hz, 1H), 6.84 (d,J=2.0 Hz, 1H), 6.81 (dd, J=5.6, 2.4 Hz, 1H), 6.67-6.65 (m, 2H), 5.13 (s,2H), 1.91 (s, 3H); MS (ESI): m/z 253.2 [M+H]⁺.

Using a procedure analogous to Example A1,4-(2-chloro-pyridin-4-yloxy)-2-fluoro-3-methyl-phenylamine (1.0 g, 3.3mmol),1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (1g, 4.8 mmol), Na₂CO₃ (0.84 g, 6.6 mmol) and Pd(PPh₃)₄ (0.25 g, 0.2 mmol)were combined to give2-fluoro-3-methyl-4-[2-(1-methyl-1H-pyrazol-4-yl)-pyridin-4-yloxy]-phenylamine(0.74 g, 75% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.27 (d, J=6.4 Hz,1H), 8.18 (s, 1H), 7.90 (s, 1H), 7.07 (s, 1H), 6.68-6.61 (m, 2H), 6.45(dd, J=5.6, 2.4 Hz, 1H), 5.06 (s, 2H), 3.82 (s, 3H), 1.95 (s, 3H); MS(ESI) m/z: 299.2 [M+H]⁺.

Example A8

To a stirred solution of NaBr (4.2 g, 0.04 mol) in SOCl₂ (300 ml, 4.0mol) was added pyridine-2-carboxylic acid (101 g, 0.81 mol)portion-wise, and the resultant mixture was heated to reflux overnight.The reaction mixture was concentrated to remove the solvent to give acrude 4-chloro-pyridine-2-carbonyl chloride (101 g) which was used inthe next step reaction without further purification.

A solution of 4-chloro-pyridine-2-carbonyl chloride (150 g, 0.857 mol)in DCM (750 ml) was slowly added to a solution of 2-methyl-propan-2-ol(158.8 g, 2.14 mol) and DMAP (21 g, 0.171 mol) in DCM (750 mL) andpyridine (750 mL). The resultant mixture was stirred at 30° C.overnight. The reaction mixture was concentrated in vacuo and theresidue was purified by chromatography to give4-chloro-pyridine-2-carboxylic acid t-butyl ester (90 g, 49% yield) as ayellow solid. ¹H NMR (CDCl₃): δ 8.63 (d, J=8.0 Hz, 1H), 8.03 (s, 1H),7.44 (d, J=8.0 Hz 1H), 1.63 (s, 9H); MS (ESI) m/z: 214 (M+H⁺).

A mixture of 4-aminophenol (2.6 g, 24 mmol) and NaH (1.1 g, 28 mmol) indry DMF (50 ml) was stirred at RT for 30 min.4-Chloro-pyridine-2-carboxylic acid t-butyl ester (5.0 g, 24 mmol) wasadded and the resulting mixture was stirred in a sealed tube at 80° C.for 12 h. The reaction mixture was concentrated in vacuo and waspurified on silica gel to give 5-(4-amino-phenoxy)-pyridine-2-carboxylicacid t-butyl ester as a yellow solid (2.4 g, 35% yield). ¹H NMR (300MHz, DMSO-d₆): δ 8.48 (d, J=5.7 Hz, 1H), 7.33 (d, J=1.8 Hz, 1H), 7.03(m, 1H), 6.84 (d, J=8.4 Hz, 1H), 6.62 (d, J=8.4 Hz, 1H), 5.18 (s, 2H),1.50 (s, 9H); MS (ESI) m/z: 287.2 (M+H⁺).

To a solution of 5-(4-amino-phenoxy)-pyridine-2-carboxylic acid t-butylester (1.0 g, 3.5 mmol) in THF (10 ml) was added aqueous NaOH (1 M, 7ml, 7 mol) followed by (Boc)₂O (0.76 g, 3.5 mmol). The resulting mixturewas heated to reflux for 2 h. The reaction mixture was concentrated, theresidue diluted with water (20 mL) and extracted with dichloromethane(3×100 mL). The combined organic layers were washed with brine, dried(Na₂SO₄), concentrated and purified via chromatography to provide5-(4-t-butoxycarbonylamino-phenoxy)-pyridine-2-carboxylic acid 1-butylester (1.2 g, 89% yield). MS (ESI) m/z: (M+H⁺) 387.3.

A solution of 5-(4-t-butoxycarbonylamino-phenoxy)-pyridine-2-carboxylicacid t-butyl ester (0.5 g, 1.3 mmol) in THF (2.0 ml) was added dropwiseto a 0° C. suspension of LiAlH₄ (0.1 g, 2.6 mmol) in dry THF (5.0 ml).The reaction was stirred at 0° C. for 2 h and was quenched with 10%aqueous NaOH (1.0 mL). The mixture was filtered and the filtrate wasconcentrated in vacuo to give[4-(6-hydroxymethyl-pyridin-3-yloxy)-phenyl]-carbamic acid t-butyl ester(0.38 g, 92% yield). MS (ESI) m/z: (M+H⁺) 317.2.

A solution of [4-(6-hydroxymethyl-pyridin-3-yloxy)-phenyl]-carbamic acidt-butyl ester (0.25 g, 0.8 mmol) in DCM (3.0 ml) was treated withactivated MnO₂ (0.42 g, 4.8 mmol) and the suspension was stirred at RTfor 2 h. The reaction suspension was filtered and the filtrate wasconcentrated in vacuo to provide[4-(6-formyl-pyridin-3-yloxy)-phenyl]-carbamic acid t-butyl ester (0.24g, 95% yield). MS (ESI) m/z: 315.0 (M+H⁺).

A solution of NaOAc (0.6 g, 7.4 mmol) in water (1.5 mL) was treated with3,3-dibromo-1,1,1-trifluoro-propan-2-one (2.2 g, 8.3 mmol) and theresulting mixture was heated to reflux for 30 min. After cooling, thesolution was added to [4-(6-formyl-pyridin-3-yloxy)-phenyl]-carbamicacidt-butyl ester (2.3 g, 7.4 mmol) in ammonium hydroxide (30%, 23 mL). Thereaction mixture was stirred at RT for 5 h, concentrated in vacuo andpurified via chromatography to give{4-[3-(4-trifluoromethyl-1H-imidazol-2-yl)-phenoxy]-phenyl}-carbamicacid t-butyl ester (2.1 g, 67% yield). MS (ESI) m/z: (M+H⁺) 421.1.

A mixture of{4-[3-(4-trifluoromethyl-1H-imidazol-2-yl)-phenoxy]-phenyl}-carbamicacid t-butyl ester (2.1 g, 2.2 mmol) and aqueous HCl (1M, 30 mL) inisopropanol (20 ml) was stirred at 90° C. for 2 h. After cooling to RT,the reaction mixture was concentrated, and the residue was partitionedwith water and dichloromethane. The organic layer was washed with brine,dried (Na₂SO₄), and concentrated to yield an HCl salt which was furtherneutralized to give4-(2-(4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yloxy)benzenamine(600 mg, 85% yield). ¹H NMR (400 MHz, CDCl₃): δ 13.48 (br s, 1H), 8.46(d, J=5.6 Hz, 1H), 7.81 (s, 1H), 7.34 (m, 1H), 6.97 (m, 1H), 6.86 (d,J=8.8 Hz, 2H), 6.66 (d, J=8.8 Hz, 2H), 5.15 (s, 2H); MS (ESI) m/z: 320(M+H⁺). MS (ESI) m/z: (M+H⁺) 321.2.

Example A9

To 60% NaH in mineral oil (0.119 g, 2.97 mmol), under an atmosphere ofargon, was added anhydrous DMF (3 mL) and the slurry was cooled in anice bath. To this suspension was added, in portions, a solution of2-chloropyridin-4-ol (0.35 g, 2.70 mmol) in DMF (2 mL). The reactionmixture was stirred cold for 5 minutes and then allowed to warm to RTand stirred for 20 minutes. 1,5-difluoro-2-methyl-4-nitrobenzene (0.514g, 2.97 mmol) was added and the reaction mixture heated at 90° C. for 3hours, cooled to RT, quenched with water and the mixture was extractedwith EtOAc (3×). The combined organic phases were washed with brine,dried (Na₂SO₄), concentrated in vacuo and purified by silica gel columnchromatography (EtOAc/hexanes) to obtain2-chloro-4-(5-fluoro-2-methyl-4-nitrophenoxy)pyridine (0.48 g, 63%yield) MS (ESI) m/z: 283.0 (M+H⁺).

To a solution of 2-chloro-4-(5-fluoro-2-methyl-4-nitrophenoxy)pyridine(0.48 g, 1.698 mmol) in ethanol (20 mL) was added Raney Ni (0.4 g). Themixture was stirred under a hydrogen atmosphere (1 atm) overnight at RT.The reaction mixture was filtered through a pad of Celite® and thefiltrate was concentrated to obtain the crude4-(2-chloropyridin-4-yloxy)-2-fluoro-5-methylbenzenamine (assuming a100% yield).

To a solution of4-(2-chloropyridin-4-yloxy)-2-fluoro-5-methylbenzenamine (0.43 g, 1.702mmol) and1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.389 g, 1.872 mmol) in DMF (20 ml) was addedtetrakis(triphenylphosphine)palladium (0.197 g, 0.170 mmol) and anaqueous solution of potassium phosphate (1.084 g, 5.11 mmol). Thereaction mixture was flushed with N₂ and then heated overnight at 90° C.Water was added and the solution was extracted with EtOAc (3×). Thecombined organic phases were washed with brine, dried (Na₂SO₄),concentrated in vacuo and purified by silica gel column chromatography(EtOAc/hexanes) to obtain5-fluoro-2-methyl-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)benzenamine(0.13 g, 25.6% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.29 (m, 1H), 8.21(s, 1H), 7.92 (s, 2H), 7.09 (m, 1H), 6.87 (m, 1H), 6.69 (m, 1H), 6.46(m, 1H), 5.10 (s, 2H), 3.84 (s, 3H), 1.93 (s, 3H); MS (ESI) m/z: 299.1(M+H⁺).

Example A10

Potassium carbonate (7.8 g, 56.4 mmol) was added to a solution of1,2,3-trifluoro-5-nitrobenzene (5 g, 28.2 mmol) and benzyl alcohol (3.2g, 29.6 mmol) in N,N-dimethylformamide (70 mL). The resultant mixturewas stirred at RT overnight. The reaction mixture was concentrated underreduced pressure and the residue was partitioned between ethyl acetateand water. The organic layer was separated and washed with brine, dried(Na₂SO₄), concentrated under reduced pressure and purified by columnchromatography to give 2-(benzyloxy)-1,3-difluoro-5-nitrobenzene (5.3 g,71% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.15 (d, J=8.4 Hz, 2H),7.46-7.37 (m, 5H), 5.39 (s, 2H).

To a solution of 2-(benzyloxy)-1,3-difluoro-5-nitrobenzene (5.3 g, 20mol) in ethanol (100 mL) was added 10% palladium on activated carbon(1.5 g). The mixture was hydrogenated (1 atm) at RT overnight. Thereaction mixture was filtered and the filtrate was concentrated underreduced pressure to give 4-amino-2,6-difluorophenol (2.9 g, 95% yield).¹H NMR (400 MHz, DMSO-d₆): δ 8.68 (brs, 1H), 6.19 (d, J=10.8 Hz, 2H),5.01 (s, 2H).

Potassium tert-butoxide (2.4 g, 22 mmol) was added to a solution of4-amino-2,6-difluorophenol (2.9 g, 20 mmol) in N,N-dimethyl-acetamide(50 mL) and the mixture was stirred at RT under nitrogen for 0.5 h. Asolution of 2,4-dichloro-pyridine (2.9 g, 20 mmol) inN,N-dimethyl-acetamide was added, and the reaction was heated to 100° C.under nitrogen for 10 h. After cooling to RT, the reaction was pouredinto water (100 mL) and the aqueous solution was extracted with ethylacetate (3×70 mL). The combined organics were washed with brine, dried(Na₂SO₄), concentrated in vacuo and purified by silica gelchromatography to give 4-(2-chloropyridin-4-yloxy)-3,5-difluoroaniline(3.0 g, 59% yield). ¹H NMR (300 MHz, DMSO-d₆): δ 8.31 (d, J=5.7 Hz, 1H),7.10 (d, J=2.1 Hz, 1H), 7.01 (dd, J=5.7 Hz, 2.1 Hz, 1H), 6.38 (d, J=10.8Hz, 2H), 5.86 (s, 2H).

To a solution of 4-(2-chloropyridin-4-yloxy)-3,5-difluoroaniline (3.0 g,11.7 mmol) in a mixture of N,N-dimethyl-formamide and water (v/v=3:1, 80mL) was added1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole(3.6 g, 17.5 mmol), potassium phosphate (4.9 g, 23.4 mmol) andtetrakis(triphenylphosphine) palladium (0.7 g, 0.6 mmol). The mixturewas degassed thoroughly, heated to 100° C. and stirred under nitrogenovernight. The solvent was removed under reduced pressure and theresidue was purified by silica gel chromatography to give3,5-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)aniline (2.6g, 74% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.36 (d, J=5.6 Hz, 1H), 8.28(s, 1H), 7.98 (s, 1H), 7.24 (d, J=2.4 Hz, 1H), 6.64 (dd, J=5.6 Hz, J=2.4Hz, 1H), 6.37 (d, J=10.8 Hz, 2H), 5.81 (s, 2H), 3.87 (s, 3H); MS (ESI):m/z 303.1 [M+H]⁺.

Example A11

4-Fluoro-2-methyl-phenol (25 g, 0.2 mol) was added to a solution ofsodium hydroxide (9.7 g, 0.24 mol) in water (160 mL) and the resultantsolution was cooled to 0° C. Methyl chloroformate (24.2 g, 0.26 mol) wasadded dropwise at 0° C. At the completion of the reaction, the pH wasadjusted to pH 8 with saturated aqueous Na₂CO₃ and then the mixture wasextracted with ethyl acetate (3×300 mL). The combined organic extractswere washed with water and brine, dried (MgSO₄) and concentrated underreduced pressure to provide carbonic acid 4-fluoro-2-methyl-phenyl estermethyl ester (30 g, 82% yield). ¹H NMR (300 MHz, DMSO-d₆): δ 7.22-7.13(m, 2H), 7.05 (m, 1H), 3.81 (s, 3H), 2.12 (s, 3H).

To a solution of carbonic acid 4-fluoro-2-methyl-phenyl ester methylester (15 g, 81.5 mmol) in conc. sulfuric acid (100 mL) at 0° C. wasadded powdered KNO₃ (8.3 g, 82.2 mmol) in several portions. The reactionmixture was stirred for 1 hour at 0° C. and was then poured into icewater and extracted with ethyl acetate (3×100 mL). The extracts werewashed with water and brine, dried (MgSO₄), concentrated in vacuo andpurified by silica gel chromatography to provide carbonic acid4-fluoro-2-methyl-5-nitro-phenyl ester methyl ester (2.0 g, 11% yield).¹H NMR (300 MHz, DMSO-d₆): δ 8.14 (d, J=6.9, 1 H), 7.60 (d, J=12.0 Hz,1H), 3.86 (s, 3H), 2.25 (s, 3H).

To a solution of aqueous sodium hydroxide (1.2 N, 20 mL, 24 mmol) wasadded 4-fluoro-2-methyl-5-nitro-phenyl ester methyl ester (2.0 g, 8.7mmol), and the resultant mixture was refluxed for 2 hours. The reactionwas cooled to RT and partitioned between EtOAc and water. The organiclayer was washed with water and brine, dried (MgSO₄), and concentratedin vacuo to provide 4-fluoro-2-methyl-5-nitro-phenol (1.4 g, 93% yield).¹H NMR (300 MHz, DMSO-d₆) δ 10.33 (s, 1H), 7.45 (d, J=6.6, 1H), 7.32 (d,J=12.3 Hz, 1H), 2.19 (s, 3H).

A mixture of 4-fluoro-2-methyl-5-nitro-phenol (1.4 g, 8.2 mmol) and 10%Pd/C (0.3 g, 20%/w) in MeOH (80 mL) was stirred under H₂ (30 psi) for 2h. The Pd/C was removed by filtration and the filtrate was concentratedto give 5-amino-4-fluoro-2-methyl-phenol (0.68 g, 62% yield). ¹H NMR(300 MHz, DMSO-d₆) δ 8.75 (s, 1H), 6.62 (d, J=12.0 Hz, 1H), 6.21 (d,J=8.1 Hz, 1H), 4.69 (s, 2H), 1.93 (s, 3H).

A mixture of 2-methanesulfonyl-4-(1-methyl-1H-pyrazol-4-yl)-pyrimidineand 2-methanesulfinyl-4-(1-methyl-1H-pyrazol-4-yl)-pyrimidine fromExample A16 (1 g, 4.2 mmol), 5-amino-4-fluoro-2-methylphenol (1.2 g, 8.5mmol) and K₂CO₃ (1.2 g, 8.6 mmol) were combined in DMF (10 mL) using aprocedure analogous to Example A10 to provide2-fluoro-4-methyl-5-(4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yloxy)benzenamine(420 mg). ¹H NMR (400 MHz, DMSO-d₆): δ 8.42 (d, J=5.2 Hz, 1H), 8.39 (s,1H), 8.07 (s, 1H), 7.40 (d, J=5.2 Hz, 1H), 6.90 (d, J=9.6 Hz, 1H), 6.47(d, J=8.4 Hz, 1H), 5.02 (br s, 2H), 3.88 (s, 3H), 1.88 (s, 3H); MS (ESI)m/z: 300.2 (M+H⁺).

Example A12

Anhydrous N,N-dimethylformamide (150 mL) was added to 60% NaH in mineraloil (2.72 g, 67.9 mmol) under an atmosphere of argon. The mixture wascooled in an ice bath and stirred. To this suspension was added,portion-wise, a solution of 2-chloropyridin-4-ol (8 g, 61.8 mmol) in DMF(30.0 mL). The reaction mixture was stirred cold for 5 minutes and thecooling bath was removed. The reaction mixture was warmed to RT andstirred for 20 minutes. 1,2,4-trifluoro-5-nitrobenzene (13.12 g, 74.1mmol) was added and the reaction mixture heated at 90° C. for 3 hours.The reaction mixture was cooled to RT. The mixture was concentrated todryness. EtOH (50 mL) and MeOH (20 mL) were added and the sample wasstirred with gentle warming and then cooled to RT. The yellow solid wascollected by filtration, and rinsed with EtOH (50 mL) and hexanes (20mL). The solid was dried under vacuum overnight to provide2-chloro-4-(2,5-difluoro-4-nitrophenoxy)pyridine as a yellow solid(11.68 g, 63% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.48 (dd, J=10.2, 7.0Hz, 1H), 8.41 (d, J=5.6 Hz, 1H), 7.90 (dd, J=11.6, 6.7 Hz, 1H), 7.41 (d,J=2.1 Hz, 1H), 7.26 (dd, J=5.6, 2.4 Hz, 1H); MS (ESI): m/z 287.0 [M+H]⁺

In a Parr Shaker flask was combined2-chloro-4-(2,5-difluoro-4-nitrophenoxy)pyridine (11.68 g, 40.8 mmol)and MeOH (200 ml) under argon. Raney Ni (50% wet, 0.955 g, 8.15 mmol)was added. The argon atmosphere was removed and replaced with hydrogen(10-20 psi) and the reaction mixture shaken under hydrogen for 4 hours.The completed reaction mixture was filtered through a pad of Celite® andthe filtrate was concentrated to dryness to provide4-(2-chloropyridin-4-yloxy)-2,5-difluoroaniline (8.2 g, 72% yield). ¹HNMR (400 MHz, DMSO-d₆): δ 8.28 (d, J=5.9 Hz, 1H), 7.25 (dd, J=11.2, 7.5Hz, 1H), 7.02 (dd, J=2.2 Hz, 1H), 6.95 (dd, J=5.8, 2.0 Hz, 1H), 6.74(dd, J=12.3, 8.3 Hz, 1H), 5.57 (s, 2H); MS (ESI): m/z 257.0 [M+H]⁺

To a solution of 4-(2-chloropyridin-4-yloxy)-2,5-difluoroaniline (450mg, 1.76 mmol) and1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(400 mg, 1.9 mmol) in N,N-dimethylformamide (30 mL) was addedtetrakis(triphenylphosphine)palladium (105 mg, 0.09 mmol) and an aqueoussolution of potassium phosphate (2 M, 1.8 mL). The mixture was flushedwith nitrogen for 10 min, and then stirred with heating at 90° C. undernitrogen overnight. After cooling to RT, the reaction mixture waspartitioned between water and ethyl acetate. The aqueous layer wasextracted with ethyl acetate (50 mL×3). The combined organic layers werewashed with brine, dried (Na₂SO₄), concentrated under reduced pressureand purified by column chromatography on silica gel to give2,5-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)aniline (335mg, 63% yield). ¹H NMR (300 MHz, DMSO-d₆): δ 8.35 (d, J=5.7 Hz, 1H),8.27 (s, 1H), 7.98 (s, 1H), 7.24-7.18 (m, 2H), 6.75 (dd, J=12.3, 8.1 Hz,1H), 6.62 (dd, J=5.4, 2.1 Hz, 1H), 5.53 (br s, 2 E), 3.87 (s, 3H); MS(ESI): m/z 303.1 [M+1]⁺.

Example A13

5-Bromo-2-nitropyridine (1 g, 4.93 mmol) was dissolved in DMF (32 ml)and cooled to 0° C. Cesium carbonate (2.408 g, 7.39 mmol) was added,followed by 2-chloro-4-hydroxypyridine (0.702 g, 5.42 mmol). The mixturewas stirred in an 80° C. oil bath for 24 hours. The reaction mixture wasthen cooled to RT, diluted with ethyl acetate (150 mL), washed withwater (2×100 mL) and brine (50 mL), dried (MgSO₄), evaporated underreduced pressure and purified via silica gel chromatography (ethylacetate-hexanes) to yield 2-chloro-4-(6-nitropyridin-3-yloxy)pyridine asa clear oil (0.540 g, 44% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.62 (d,1H), 8.41 (m, 2H), 8.06 (d, 1H), 7.37 (d, 1H), 7.23 (dd, 1H); MS (ESI)m/z: 252.0 (M+H⁺).

2-Chloro-4-(6-nitropyridin-3-yloxy)pyridine (0.540 g, 2.146 mmol) wasdissolved in THF (54 ml) and MeOH (54 ml). Ammonium chloride (1.148 g,21.46 mmol) was then added, followed by zinc dust (1.403 g, 21.46 mmol).The reaction was stirred at RT for 45 minutes, filtered over Celite® andconcentrated under reduced pressure to yield5-(2-chloropyridin-4-yloxy)pyridin-2-amine as a brown solid (0.49 g,99%). It was used as is in the next reaction. ¹H NMR (400 MHz, DMSO-d₆):δ 8.46 (d, 1H), 7.81 (d, 1H), 7.30 (dd, 1H), 6.90 (m, 2H), 6.50 (d, 1H),6.08 (s, 2H); MS (ESI) m/z: 222.0 (M+H⁺).

5-(2-Chloropyridin-4-yloxy)pyridin-2-amine (0.47 g, 2.121 mmol) wasdissolved in DMF (11 ml). Water (3.67 ml) was added to the mixture,followed by1-methyl-4(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-pyrazole(0.662 g, 3.18 mmol), and cesium carbonate (2.63 g, 8.06 mmol). Argonwas bubbled through the mixture for several minutes, and then palladiumtetrakistriphenylphosphine (0.245 g, 0.212 mmol) was added. The flaskwas fitted with a condenser and argon was flushed through the system.The reaction mixture was then placed in a 90° C. oil bath under aballoon of argon and heated for 23 hours. The solution was then cooledto RT and diluted with THF (75 mL) and washed with brine (2×50 mL). Thecombined aqueous layers were then back extracted with THF (40 mL). Thecombined organic layers were dried (MgSO₄), concentrated under reducedpressure and purified via silica gel chromatography (THF-ethyl acetate)to yield 5-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)pyridin-2-amineas an off-white solid (0.357 g, 63% yield). ¹H NMR (400 MHz, DMSO-d₆): δ8.31 (d, 1H), 8.22 (s, 1H), 7.92 (s, 1H), 7.80 (d, 1H), 7.27 (dd, 1H),7.14 (d, 1H), 6.85 (s, 6.57 (dd, 1H), 6.01 (s, 2H), 3.84 (s, 3H); MS(ESI) m/z: 268.1 (M+H⁺).

Example A14

Sodium hydride (60% in mineral oil) (0.620 g, 15.5 mmol) was placed in a100 mL round bottom flask under argon. Dry DMF (30 mL) was added,followed by portion wise addition of 2-chloro-4-hydroxypyridine (1.339g, 10.33 mmol) at 0° C. The mixture was stirred at 0° C. for 30 minutes,and then slowly warmed to RT. A solution of5-chloro-2,4-difluoronitrobenzene (2 g, 10.33 mmol) in DMF (4.4 mL) wasadded to the suspension, and the mixture was placed in a 90° C. oil bathto heat for 15 hours under argon. The reaction mixture was then cooledto RT and diluted with ethyl acetate (100 mL), washed with 10% aqueousLiCl (3×100 mL) and brine (2×100 mL), dried (MgSO₄) and purified viasilica gel chromatography (ethyl acetate/hexanes) to yield2-chloro-4-(2-chloro-5-fluoro-4-nitrophenoxy)pyridine as a bright yellowoil (1.415 g, 45% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.56 (dd, 1H),8.35 (dd, 1H), 7.88 (dd, 1H), 7.32 (dd, 1H), 7.18 (m, 1H); MS (ESI) m/z:303.0 (M+H⁺).

2-Chloro-4-(2-chloro-5-fluoro-4-nitrophenoxy)pyridine (1.306 g, 4.31mmol) was dissolved in THF (108 ml) and MeOH (108 ml). Ammonium chloride(2.305 g, 43.1 mmol) was then added, followed by zinc dust (2.82 g, 43.1mmol). The reaction mixture was stirred for 1 hour at RT. The solidswere filtered over Celite® and the solution was concentrated underreduced pressure to yield5-chloro-4-(2-chloropyridin-4-yloxy)-2-fluorobenzenamine as a brownsolid which was used without purification assuming a 100% yield. MS(ESI) m/z: 273.0 (M+H⁺).

5-Chloro-4-(2-chloropyridin-4-yloxy)-2-fluorobenzenamine (1.177 g, 4.31mmol) and1-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.166g, 5.60 mmol) were dissolved in DMF (16.16 ml), cesium carbonate (4.21g, 12.93 mmol) was added, followed by water (5.39 ml). Argon was bubbledthrough the mixture for 5 minutes, and then palladiumtetrakistriphenylphosphine (0.249 g, 0.215 mmol) was added. The flaskwas fitted with a reflux condenser, flushed with argon, and heated in a90° C. oil bath under a balloon of argon for 4 hours. The reactionmixture was then cooled to RT and diluted with a 4:1 mixture of ethylacetate and THF. The solution was extracted with 10% aqueous LiCl (2×150mL) and brine (100 mL), dried (MgSO₄), evaporated under reduced pressureand purified via silica gel chromatography (ethyl acetate/hexanes) toyield5-chloro-2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)benzenamineas a tan solid (1.062 g, 77% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.31(d, 1H), 8.24 (s, 1H), 7.95 (s, 1H), 7.20 (d, 1H), 7.13 (d, 1H), 6.92(d, 1H), 6.52 (dd, 1H), 5.49 (s, 2H), 3.84 (s, 3H); MS (ESI) m/z: 319.1(M+H⁺).

Example A15

Sodium hydride (136 mg, 3.4 mmol, 60% in mineral) was added to a 0° C.solution of 2-chloropyridin-4-ol (2 g, 15.4 mmol) in DMF (38 mL) underAr. The mixture was stirred at 0° C. for 1 h. A solution of1,2,4-trifluoro-5-nitrobenzene (626 mg, 3.1 mmol) in DMF (7.6 ml) wasadded and the reaction was stirred under Ar at 90° C. for 3 h. Themixture was cooled to RT and stirred overnight. The solvent was removedunder reduced pressure and the crude product was partitioned betweenwater (50 ml) and EtOAc (50 ml). The mixture was extracted with EtOAc(3×50 ml). The combined organic extracts were washed with brine, dried(Na₂SO₄), concentrated under reduced pressure and purified by silica gelcolumn chromatography (hexanes/EtOAc) to yield2-chloro-4-(2,5-difluoro-4-nitrophenoxy)pyridine (3.57 g, 81% yield). ¹HNMR (400 MHz, DMSO-d₆): δ 8.43-8.33 (m, 2H), 7.85-7.79 (m, 1H), 7.33 (d,1H), 7.20-7.18 (m, 1H); MS (ESI) m/z: 287.0 (M+H⁺).

A mixture of 2-chloro-4-(2,5-difluoro-4-nitrophenoxy)pyridine (3.57 g,2.1 mmol), zinc dust (8.14 g, 125 mmol) and ammonium chloride (6.66 g,125 mmol) in THF (160 mL) and MeOH (160 ml) was stirred at RT for 2 h.The reaction mixture was filtered and the filtrate was concentratedunder reduced pressure. The crude product was partitioned between EtOAc(50 ml) and a mixture of water and saturated NaHCO₃ (aq) (1:1; 50 ml).The mixture was extracted with EtOAc (2×50 ml). The combined organicextracts were dried (Na₂SO₄) and evaporated to yield4-(2-chloropyridin-4-yloxy)-2,5-difluoroaniline (3.18 g, 100% yield). ¹HNMR (400 MHz, DMSO-d₆): δ 8.26 (d, 1H), 7.24-7.19 (m, 1H), 7.00 (s, 1H),6.94-6.92 (m, 1H), 6.74-6.69 (m, 1H), 5.54 (brs, 2H); MS (ESI) m/z:257.0 (M+H⁺).

3-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole(0.3 g, 1.442 mmol) and potassium carbonate (0.996 g, 7.21 mmol) weresuspended in acetonitrile (10 ml) and stirred overnight at RT.Additional iodomethane (0.5 ml) was added and the mixture was stirredovernight at RT. The mixture was diluted with EtOAc and the inorganicsalts were removed by filtration. The filtrate was evaporated to yieldan inseparable mixture (2:1) of1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleand1,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.267 g, 83% yield). MS (ESI) m/z: 223.1 (M+H⁺).

In a sealed tube, 4-(2-chloropyridin-4-yloxy)-2,5-difluoroaniline (0.257g, 1.00 mmol), a (2:1) mixture of1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleand1,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.267 g, 1.20 mmol), potassium carbonate (0.415 g, 3.01 mmol) andtetrakistriphenylphosphine palladium(0) (0.058 g, 0.050 mmol) weresuspended in a mixture of dioxane (10 ml) and water (1.667 ml). Themixture was degassed with Ar and heated at 90° C. overnight. Thereaction was diluted with saturated aq. NaHCO₃ (25 ml) and extractedwith EtOAc (3×25 ml). The combined organic extracts were concentrated invacuo and purified by silica gel chromatography (hexanes/EtOAc) to elutean inseparable (2:1) mixture of4-(2-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorobenzenamineand4-(2-(1,5-dimethyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorobenzenamine(0.31 g, 98% yield). MS (ESI) m/z: 317.1 (M+H⁺).

Example A16

Methyl chloroformate (77.3 g, 0.82 mol) was added dropwise to a −10° C.solution of 2-chloro-4-fluorophenol (100 g, 0.68 mol) and sodiumhydroxide (32.8 g, 0.82 mol) in water (550 mL). After complete addition,the precipitated solid was collected by filtration and washed with waterto give 2-chloro-4-fluorophenyl methyl carbonate (110 g, 79% yield). ¹HNMR (300 MHz, DMSO-d₆): δ 7.62 (dd, J=8.1, 2.7 Hz, 1H), 7.50 (dd, J=9.0,5.4 Hz, 1H), 7.30 (td, J=8.1, 3.0 Hz, 1H), 3.86 (s, 3H); MS (ESI) m/z:205.2 (M+H⁺).

To a suspension of 2-chloro-4-fluorophenyl methyl carbonate (110 g, 0.54mol) in conc. H₂SO₄ (50 mL) was slowly added a mixture comprised ofcone. H₂SO₄ (40 mL) and fuming HNO₃ (40.8 mL, 0.89 mol). The resultantmixture was stirred for 30 min at 0° C. The reaction mixture was pouredinto ice water and the precipitated solid was collected by filtation andwashed with water to give 2-chloro-4-fluoro-5-nitrophenyl methylcarbonate (120 g, 90% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.45 (d,J=7.2 Hz, 1H), 8.12 (d, J=10.8 Hz, 1H), 3.89 (s, 3H); MS (ESI) m/z:250.1 (MAI).

2-Chloro-4-fluoro-5-nitrophenyl methyl carbonate (120 g 0.48 mol) wascombined with a solution of sodium hydroxide (22.7 g, 0.57 mol) in water(300 mL) and the resultant mixture was refluxed for 4 h. The insolublesolids were removed by filtration and the filtrate was acidified withdilute HCl. The precipitated solid was collected by filtration andwashed with water to give 2-chloro-4-fluoro-5-nitrophenol (90 g, 98%yield). ¹H NMR (400 MHz, DMSO-d₆): δ 11.18 (s, 1H), 8.10 (d, J=10.4 Hz,1H), 7.62 (d, J=7.2 Hz, 1H); MS (ESI) m/z: 192.1 (M+H⁺).

2-Chloro-4-fluoro-5-nitrophenol (85 g, 0.45 mol) and 10% Pd/C (25 g,0.023 mol) were combined in EtOH and hydrogenated (50 psi) for 12 h. Thereaction mixture was filtered. The filtrate was concentrated in vacuoand purified by silica gel chromatography to provide3-amino-4-fluorophenol (40 g 70% yield). ¹H NMR (400 MHz, DMSO-d₆): δ8.87 (s, 1H), 6.70 (dd, J=11.2, 8.8 Hz, 1H), 6.14 (dd, J=7.8, 2.4 Hz,1H), 5.84 (m, 1H), 4.92 (s, 2H); MS (ESI) m/z: 128.2 (M+H⁺).

4-Chloro-2-methylsulfanyl-pyrimidine (1.4 g, 8.8 mmol),1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole(2.0 g, 1.1 eq), Na₂CO₃ (2.8 g, 3 eq) and Pd(PPh₃)₄ (500 mg, 0.43 mmol)were combined in a solvent comprised of toluene/EtOH/H₂O (4/4/1, 20 mL).The reaction mixture was purged with argon and heated to 100° C.overnight. The reaction was filtered to remove insolubles and thefiltrate was concentrated in vacuo. The residue was purified by silicagel chromatography to provide4-(1-methyl-1H-pyrazol-4-yl)-2-(methylthio)pyrimidine contaminated withtriphenylphoshine oxide (2.0 g, >100% yield). ¹H NMR (300 MHz, DMSO-d₆):δ 8.49 (d, J=5.1 Hz, 1H), 8.46 (s, 1H), 8.12 (s, 1H), 7.38 (d, J=5.1 Hz,1H), 3.89 (s, 3H), 2.52 (s, 3H).

A solution of 4-(1-methyl-1H-pyrazol-4-yl)-2-methylsulfanyl-pyrimidine(2.0 g crude, 8.8 mmol) in dichloromethane (20 mL) was treated withm-CPBA (3.0 g, 17.4 mmol) portionwise at RT. The reaction was stirred 2h and was quenched with saturated aqueous NaS₂SO₃ (3 mL). The mixturewas partitioned with saturated aq Na₂CO₃ and the organics were washedwith brine, dried (Na₂SO₄), and concentrated to provide a mixture (2.0g) of 2-methanesulfonyl-4-(1-methyl-1H-pyrazol-4-yl)-pyrimidine and2-methanesulfinyl-4-(1-methyl-1H-pyrazol-4-yl)-pyrimidine with a molarratio of 1:0.3. ¹H NMR (400 MHz, DMSO-d₆): δ 8.83 (d, J=5.2 Hz, 1H),8.82 (d, J=5.2 Hz, 0.24H), 8.57 (s, 1H), 8.57 (s, 0.24H), 8.21 (s, 1H),8.21 (s, 0.23H), 7.80 (d, J=5.6 Hz, 1H), 7.80 (d, J=5.6 Hz, 0.25H), 3.48(s, 3H), 2.88 (s, 0.7H).

The above mixture of2-methanesulfonyl-4-(1-methyl-1H-pyrazol-4-yl)-pyrimidine and2-methanesulfinyl-4-(1-methyl-1H-pyrazol-4-yl)-pyrimidine (1 g, 4.2mmol), 4-amino-3-fluoro-phenol (1.1 g, 8.6 mmol) and K₂CO₃ (1.2 g, 8.6mmol) in DMF (10 mL) was heated at 100° C. for 12 h. The reaction waspartitioned between H₂O and EtOAc (3×50 mL). The combined organics weredried (Na₂SO₄), concentrated in vacuo and chromatographed to provide2-fluoro-5-(4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yloxy)benzenamine(402 mg). ¹H NMR (400 MHz, DMSO-d₆): δ 8.44 (d, J=5.2 Hz, 1H), 8.39 (s,1H), 8.07 (s, 1H), 7.41 (d, J=5.2 Hz, 1H), 6.98 (t, J=9.6 Hz, 1H), 6.53(dd, J=5.6, 2.0 Hz, 1H), 6.28 (d, J=8.4 Hz, 1H), 5.25 (br s, 2H), 3.88(s, 3H). MS (ESI) m/z: 286.2 (M+H⁺).

Example A17

Sulfuric acid (10 mL) was cooled to 0° C. and hydrogen peroxide (4.92ml, 48.1 mmol) was added slowly, maintaining an internal temperature ofless than 20° C. A solution of 2-amino-5-bromo-4-methylpyridine (1.5 g,8.02 mmol) in 10 mL of sulfuric acid was then added. The mixture wasstirred in the ice bath for 45 minutes, and then warmed to RT. After 1hour at RT the color of the reaction mixture gradually changed fromgrass green to bright yellow. The reaction mixture was poured over ice(100 mL) and the solid that formed was collected via suction filtrationand washed with water. The light orange solid was dried overnight toyield 5-bromo-4-methyl-2-nitropyridine (1.08 g, 62% yield), which wasused without further purification. ¹H NMR (400 MHz, DMSO-d₆): δ 8.77 (s,1H), 8.38 (s, 1H), 2.51 (s, 3H).

2-Chloro-4-hydroxypyridine (0.239 g, 1.843 mmol) was dissolved in DMF(18.43 ml) and potassium t-butoxide (0.290 g, 2.58 mmol) was added. Thesolution was degassed for several minutes, and then5-bromo-4-methyl-2-nitropyridine (0.4 g, 1.843 mmol) was added. Themixture was heated at 65° C. for 70 hours under argon and then at 80° C.for 24 hours. The reaction mixture was cooled to RT, diluted with ethylacetate (150 mL), washed with water (75 mL), 10% aqueous LiCl (2×75 mL),saturated aqueous bicarbonate (75 mL) and brine (75 mL), dried (MgSO₄),evaporated and purified via silica gel chromatography (ethylacetate/hexanes) to yield2-chloro-4-(4-methyl-6-nitropyridin-3-yloxy)pyridine as a yellow solid(0.087 g, 18% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.49 (s, 1H), 8.47(s, 1H), 8.35 (d, 1H), 7.24 (d, 1H), 7.12 (dd, 1H), 2.31 (s, 3H); MS(ESI) m/z: 266.0 (M+H⁺).

2-Chloro-4-(4-methyl-6-nitropyridin-3-yloxy)pyridine was dissolved inTHF (11.95 ml)/methanol (11.95 ml) and ammonium chloride (0.256 g, 4.78mmol) was added, followed by zinc dust (0.313 g, 4.78 mmol). The mixturestirred at RT for 1.5 hours before it was filtered through Celite®. Thefiltrate was evaporated under reduced pressure to yield a magenta filmwhich was partitioned between ethyl acetate/THF (4:1) and water. Theorganic layer was washed with brine, dried (MgSO₄) and evaporated toyield 5-(2-chloropyridin-4-yloxy)-4-methylpyridin-2-amine as a brown oil(0.116 g, 103%), which was used in the next step without purification.MS (ESI) m/z: 236.1 (M+H⁺).

5-(2-chloropyridin-4-yloxy)-4-methylpyridin-2-amine (0.116 g, 0.492mmol) was dissolved in DMF (2 ml) and 1-methyl-1H-pyrazole-4-boronicacid pinacol ester (0.154 g, 0.738 mmol) was added, followed by cesiumcarbonate (0.481 g, 1.477 mmol) and water (0.667 ml). Argon was bubbledthrough the mixture for several minutes, and then palladiumtetrakistriphenylphosphine (0.028 g, 0.025 mmol) was added. The flaskwas fitted with a reflux condenser, flushed with argon, and heated undera balloon of argon at 90° C. for 16 hours. The mixture was then cooledto RT, and the solution was diluted with a 4:1 mix of ethyl acetate andTHF (70 mL). It was washed with 10% aqueous LiCl (2×50 mL) and brine (50mL), dried (MgSO₄), evaporated in vacuo and purified via silica gelchromatography (DCM/MeOH) to yield4-methyl-5-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)pyridin-2-amineas a clear oil (0.084 g, 61% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.30(d, 1H), 8.22 (s, 1H), 7.93 (s, 1H), 7.69 (s, 1H), 7.11 (d, 1H), 6.50(dd, 1H), 6.38 (s, 1H), 5.89 (s, 2H), 3.84 (s, 3H), 1.95 (s, 3H); MS(ESI) m/z: 282.1 (M+H⁺).

Example A18

4-Chloro-2-methylsulfanyl-pyrimidine (1.4 g, 8.8 mmol),4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (2.0 g,10.3 mmol), Na₂CO₃ (2.8 g, 26.4) and Pd(PPh₃)₄ (500 mg, 0.43 mmol) werecombined in a solvent comprised of toluene/EtOH/H₂O (4/4/1, 20 mL). Themixture was degassed by applying a vacuum and backfilling the headspacewith argon. The reaction mixture was heated overnight at 100° C. Theinsoluble portion was filtered and the filtrate was concentrated andpurified by silica gel chromatography to provide2-(methylthio)-4-(1H-pyrazol-4-yl)pyrimidine (1.2 g, 71% yield). ¹H NMR(400 MHz, CDCl₃) δ 8.45=6.4 Hz, 1H), 8.24 (s, 1H), 7.23 (s, 1H), 7.05(d, J=6.4 Hz, 1H), 2.51 (s, 3H).

To a solution of 2-(methylthio)-4-(1H-pyrazol-4-yl)pyrimidine (200 mg, 1mmol) in dichloromethane (3 mL) and H₂O (1 mL) was added4-methoxybenzylchloride (200 mg, 1.28 mmol) at 0° C. The mixture wasstirred at R1 overnight. The organic layer was separated, washed withbrine and concentrated in vacuo to give crude4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-2-(methylthio)pyrimidine. ¹H NMR(300 MHz, DMSO-d₆) δ 8.58 (s, 1H), 8.50, (d, J=5.4 Hz, 1H), 8.16 (s,1H), 7.40 (d, J=5.4 Hz, 1H), 7.27 (d, J=8.4 Hz, 2H), 7.22 (d, J=8.4 Hz,2H), 5.30 (s, 2H), 3.72 (s, 3H), 2.51 (s, 3H); MS (ESI) m/z: 313 (M+H⁺).

To a solution of4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-2-(methylthio)pyrimidine (200mg, 0.64 mmol) in dichloromethane was added m-CPBA (220 mg, 1.28 mmol).The reaction was stirred for 2 hour at RT. Water was added, the organiclayer was separated and the aqueous layer was extracted withdichloromethane. The combined organics were washed with brine andconcentrated in vacuo. The residue was combined with3-amino-4-fluorophenol (165 mg, 1.28 mmol) and K₂CO₃ (176 mg, 1.28 mmol)in DMF (5 mL) and the resultant mixture was heated at 90° C. overnight.After filtration and concentration, the residue was purified by silicagel column chromatography to give5-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrimidin-2-yloxy)-2-fluorobenzenamine(210 mg, 84% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 8.50 (s, 1H), 8.44, (d,J=5.4 Hz, 1H), 8.10 (s, 1H), 7.42 (d, J=5.4 Hz, 1H), 7.25 (d, J=8.4 Hz,2H), 6.98 (t, J=9.6 Hz, 1H), 6.91 (d, J=8.4 Hz, 2H), 6.52 (dd, J=2.7,8.7 Hz, 1H), 6.28 (m, 1H), 5.30 (br s, 2H), 5.26 (s, 2H), 3.72 (s, 3H);MS (ESI) m/z: 392.2 (M+H⁺).

To a solution of5-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrimidin-2-yloxy)-2-fluorobenzenamine(50 mg, 0.13 mmol) in dichloromethane (3 mL) was added TFA (0.3 mL) at0° C. and the reaction stirred at RT for 12 h. The solvent was removedin vacuo, the residue was washed with ether and treated with saturatedammonia solution. The solid was collected via filtration and dried undervacuum to give5-(4-(1H-pyrazol-4-yl)pyrimidin-2-yloxy)-2-fluorobenzenamine (15 mg, 43%yield). ¹H NMR (300 MHz, MeOD) δ 8.44 (d, J=5.1 Hz, 1H), 8.23 (br s,2H), 7.40 (d, J=5.4, 1 H), 7.02 (dd, J=10.8, 8.7 Hz, 1H), 6.73 (dd,J=2.7, 7.2 Hz, 1H), 6.50 (m, 1H); MS (ESI) m/z: 272.2 (M+H⁺).

Example A19

2,5-Difluoro-4-nitro-phenol (1.739 g, 9.93 mmol) and3-bromo-4-chloro-pyridine (0.637 g, 3.31 mmol) were dissolved inchlorobenzene (6 ml) and heated at 145° C. overnight. The solvent wasremoved under reduced pressure and the residue partitioned between EtOAcand 10% K₂CO₃ _((aq)) . The mixture was extracted with EtOAc (2×). Thecombined organic extracts were washed with 10% K₂CO₃ _((aq)) and brine,dried, evaporated and purified by silica gel chromatography(hexanes/EtOAc) to yield 3-bromo-4-(2,5-difluoro-4-nitrophenoxy)pyridine(414 mg, 38% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.84 (s, 1H),8.51-8.45 (m, 2H), 7.82-7.78 (m, 1H), 7.22 (d, 1H); MS (ESI) m/z: 331.0(M+H⁺).

3-Bromo-4-(2,5-difluoro-4-nitrophenoxy)pyridine (0.414 g, 1.25 mmol) wasdissolved in EtOH (30 ml). Tin (II) chloride dihydrate (1.129 g, 5.00mmol) was added and the mixture was heated at 80° C. for 4 h. Thesolvent was removed under reduced pressure and the residue quenched withsat. NaHCO₃ _((aq)) . The mixture was diluted with EtOAc and filteredthrough Celite®. The Celite bed was washed with water (2×) and EtOAc(2×). The filtrate was extracted with EtOAc (2×). The combined organicextracts were dried and evaporated to yield4-(3-bromopyridin-4-yloxy)-2,5-difluorobenzenamine (0.42 g, 112% yield).¹H NMR (400 MHz, DMSO-d₆): δ 8.68 (s, 1H), 8.33 (d, 1H), 7.28-7.23 (m,1H), 6.76-6.71 (m, 2H), 5.56 (br s, 2H); MS (ESI) m/z: 301.0 (M+H⁺).

In a sealed tube, 4-(3-bromopyridin-4-yloxy)-2,5-difluorobenzenamine(0.42 g, 1.395 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.363 g, 1.744 mmol), potassium carbonate (0.578 g, 4.18 mmol), andtetrakistriphenylphosphine palladium (0) (0.081 g, 0.070 mmol) weresuspended in dioxane (8 ml) and water (1.333 ml). The mixture wasdegassed with Ar and heated at 90° C. overnight. The reaction mixturewas cooled and partitioned between EtOAc and sat. NaHCO₃ _((aq)) . Themixture was extracted with EtOAc (3×). The combined organic extractswere dried, evaporated and purified by silica gel chromatography(hexanes/EtOAc) to yield2,5-difluoro-4-(3-(1-methyl-1,1-pyrazol-4-yl)pyridin-4-yloxy)benzenamine(272 mg, 65% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.80 (s, 1H) 8.22-8.20(m, 214), 8.00 (s, 1H), 7.24-7.19 (m, 1H), 6.76-6.71 (m, 1H), 6.62 (d,1H), 5.50 (br s, 2H), 3.78 (s, 3H); MS (ESI) m/z: 301.0 (M+H⁺).

Example A20

To a solution of4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-2-(methylthio)pyrimidine fromExample A18 (200 mg, 0.64 mmol) in dichloromethane was added m-CPBA (220mg, 1.28 mmol). The reaction was stirred for 2 hour at RT. Water wasadded, the organic layer was separated and the aqueous layer wasextracted with dichloromethane. The combined organics were washed withbrine and concentrated in vacuo. The residue was combined with5-amino-4-fluoro-2-methylphenol (180 mg, 1.28 mmol) and K₂CO₃ (176 mg,1.28 mmol) in DMF (5 mL) and the resultant mixture was heated at 90° C.overnight. After filtration and concentration, the residue was purifiedby silica gel column chromatography to give5-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrimidin-2-yloxy)-2-fluoro-4-methylbenzenamine(210 mg, 84% yield). MS (ESI) m/z: 406.2 (M+H).

A solution of5-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrimidin-2-yloxy)-2-fluoro-4-methylbenzenamine(0.5 g, 1.2 mmol) in dichloromethane (20 mL) was treated with TFA (5 mL)at 0° C. The mixture was then stirred at RT for 12 h. The solvent wasremoved in vacuo, the residue was washed with ether and treated withsaturated ammonia solution. The solid was collected via filtration anddried under vacuum to give5-(4-(1H-pyrazol-4-yl)pyrimidin-2-yloxy)-2-fluoro-4-methylbenzenamine(240 mg, 68%, yield). ¹H NMR (400 MHz, MeOD): δ 8.41 (d, J=5.2 Hz, 1H),8.21 (br s, 2H), 7.40 (d, J=5.2, 1H), 6.90 (d, J=11.6 Hz, 1H), 6.62 (d,J=8.0 Hz, 1H), 1.99 (s, 3H). MS (ESI) m/z: 286.1 (M+H⁺).

Example A21

To a degassed solution of 4-(2-chloropyridin-4-yloxy)-2-fluoroanilinefrom Example A1 (0.801 g, 3.36 mmol) in DMF (2 mL) and TEA (2 mL) wasadded ethynyltrimethylsilane (0.929 ml, 6.71 mmol),trans-dichloro-bis(triphenyl phosphine) palladium(0) (0.236 g, 0.336mmol) and copper (I) iodide (0.064 g, 0.336 mmol) and the mixture wasstirred at 90° C. for 16 h. Water (60 ml) was added to the mixture,product was extracted with EtOAc (2×45 ml) and the combined organicswere washed with brine, dried (Na₂SO₄) and concentrated to afford crudeproduct. The product was dissolved in methanol (10 ml), K₂CO₃ (0.5 g)was added and the mixture was stirred at RT for 2 h. Solvent wasremoved, water (60 mL) and EtOAc (40 ml) were added, the layers wereseparated and the aqueous layer was extracted with EtOAc (1×30 mL). Thecombined organic layer was washed with brine, dried (Na₂SO₄),concentrated and purified by column chromatography(ethylacetate/hexanes) to afford4-(2-ethynylpyridin-4-yloxy)-2-fluorobenzenamine as a thick residue(0.56 g, 73% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.37 (d, J=6.0 Hz,1H), 6.98 (dd, J=8.0 Hz, 2.4 Hz, 1H), 6.95 (d, J=6.0 Hz, 1H), 6.87 (dd,J=6.0 Hz, 2.4 Hz, 1H), 6.81-6.73 (m, 2H), 5.20 (brs, 2H), 4.03 (s, 1H);MS (ESI) m/z: 229.1 (M+H⁺).

Acetaldoxime (0.078 g, 1.321 mmol) and triethylamine (0.246 ml, 1.761mmol) were added to a solution of4-(2-ethynylpyridin-4-yloxy)-2-fluorobenzenamine (0.201 g, 0.881 mmol)in THF (4 mL) in a microwave reaction vial. To this solution was added1-chloropyrrolidine-2,5-dione (0.176 g, 1.32 mmol) and the mixture wasstirred at 130° C. for 45 min under microwave irradiation. An additional1.5 eq each of acetaldoxime and 1-chloropyrrolidine-2,5-dione were addedand the reaction heated for an additional 45 min at 130° C. This processwas repeated one more time. The mixture was poured into a biphasicsolution of water (40 mL) and EtOAc (30 mL). The organic layer wasseparated and the aqueous layer was extracted with EtOAc (2×20 ml). Thecombined organics were washed with brine, dried (Na₂SO₄), concentratedin vacuo and purified by column chromatography (EtOAc-hexanes) to afford2-fluoro-4-(2-(3-methylisoxazol-5-yl)pyridin-4-yloxy)benzenamine (58 mg,23% yield) as light red colored residue. MS (ESI) m/z: 286.1 (M+H⁺).

Example A22

Using a procedure analogous to Example A1, 5-amino-2-hydroxypyridine(10.15 g, 92 mmol) and 2,4-dichloropyridine (13.64 g, 92 mmol) werecombined to provide 6-(2-chloropyridin-4-yloxy)pyridin-3-amine (7.09 g,35% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.12 (m, 1H), 7.61 (m, 1H),7.26 (m, 1H), 7.0 (s, 1H), 6.97-6.94 (m, 2H), 5.4 (brs, 214); MS (ESI)m/z: 222.0 (M+H⁺).

Using a procedure analogous to Example A13,6-(2-chloropyridin-4-yloxy)pyridin-3-amine (6.06 g, 27.3 mmol) and1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(8.53 g, 41.0 mmol) were combined to provide6-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)pyridin-3-amine (4.67 g,64% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.3 (m, 1H), 8.2 (s, 1H), 7.98(s, 1H), 7.65 (s, 1H), 7.3 (s, 1H), 7.25-7.2 (m, 1H), 6.85-6.81 (m, 1H),6.6-6.55 (m, 1H), 5.3 (s, 2H), 3.8 (s, 3H); MS (ESI) m/z: 268.1 (M+H⁺).

Example A23

Sodium azide (1.942 g, 29.9 mmol) was added to a suspension ofchloromethyl pivalate (3.00 g, 19.92 mmol) in water (5 mL) and stirredvigorously at 90° C. for 16 h. The reaction mixture was diluted withwater (20 mL) and EtOAc (20 ml). The organic layer was washed withbrine, dried (Na₂SO₄) and concentrated to afford azidomethyl pivalate asa liquid (2 g, 64% yield). ¹H NMR (400 MHz, Acetone-d₆): δ 5.23 (s, 2H),1.22 (s, 9H).

To a suspension of azidomethyl pivalate (0.075 g, 0.477 mmol),4-(2-ethynylpyridin-4-yloxy)-2-fluorobenzenamine from Example A21 (0.109g, 0.477 mmol) in t-butanol (0.6 mL) and water (0.6 mL) was added sodiumascorbate (0.021 g, 0.095 mmol). Copper(II)sulfate in water (0.048 ml,0.048 mmol) was added to the above suspension and the dark red mixturewas stirred for 3 h at RT. It was diluted with water (30 mL) and EtOAc(20 mL), the layers were separated and the aqueous layer was extractedwith EtOAc (2×15 mL). The combined organics were washed with brine,dried (Na₂SO₄) and concentrated to afford(4-(4-(4-amino-3-fluorophenoxy)pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methylpivalate as a red solid. (0.165 g, 90% yield). ¹H NMR (400 MHz,DMSO-d₆): δ 8.54 (s, 1H), 8.46 (brs, 1H), 7.60 (s, 1H), 6.98 (d, J=8.8Hz, 1H), 6.94 (d, J=3.6 Hz, 1H), 6.83-6.81 (m, 2H), 6.42 (s, 2H), 4.78(s, 2H), 1.17 (s, 9H); MS (ESI) m/z: 386.1 (M+H⁺).

Example B1

A solution of 1,1-cyclopropanedicarboxylic acid (3.07 g, 23.60 mmol) inTHF (40 mL) was cooled to 0° C. and treated with Et₃N (3.30 mL, 23.7mmol) and thionyl chloride (1.72 mL, 23.6 mmol). The resultant reactionmixture was stirred 30 min at 0° C. 4-Fluoroaniline (2.30 mL, 23.9 mmol)was added and the reaction mixture was allowed to slowly warm to RTovernight. The slurry was diluted with EtOAc (200 mL) and was extractedinto 1 N aq NaOH (3×60 mL). The aqueous portion was washed with ether(50 mL) and acidified to pH 1-2 with 6 N aq HCl. The resultingprecipitate was collected by filtration and washed with water. Theremaining solids were dissolved in a mixture of acetonitrile-MeOH andthe solution was concentrated in vacuo until precipitation began.Complete dissolution was affected by warming to 70° C. The resultantsolution was allowed to cool to RT overnight to provide large crystals.The crystals were isolated by filtration, washed with acetonitrile anddried in vacuo to provide1-((4-fluorophenyl)carbamoyl)cyclopropanecarboxylic acid (1.76 g). Themother liquors were concentrated to initiate a second crystallization,which provided an additional crop of1-((4-fluorophenyl)carbamoyl)cyclopropanecarboxylic acid (1.39 g, 60%yield overall). ¹H NMR (400 MHz, DMSO-d₆): δ 13.06 (s, 1H), 10.55 (s,1H), 7.60 (m, 2H), 7.12 (m, 2H), 1.39 (s, 4H); MS (ESI) m/z: 224.1(M+H⁺).

Example B2

A solution of 1,1-cyclopropanecarboxylic acid (0.23 g, 1.74 mmol) in THF(5 mL) was cooled to 0° C. and treated with triethylamine (0.48 ml, 3.47mmol) and thionyl chloride (0.13 ml, 1.74 mmol). The reaction mixturewas stirred 30 min at 0° C. A solution of Example A3 (0.5 g, 1.65 mmol)in THF (5 mL) was added. The reaction mixture was stirred at 0° C. for 1h and then stirred overnight at RT. The reaction mixture was treatedwith 1 M HCl, and then EtOAc was added. The resultant precipitate wascollected by filtration, washed with EtOAc, and dried under vacuum toobtain1-((2,3-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)carbamoyl)cyclopropanecarboxylicacid (60% purity, 0.6 g, 53% yield). MS (ESI) m/z: 415.1 (M+H⁺). Thismaterial was used without further purification.

Example B3

To a stirring solution of 1,1-cyclopropanedicarboxylic acid (0.178 g,1.367 mmol) in THF (4 ml) at 0° C. was added Et₃N (0.190 ml, 1.367 mmol)followed by thionyl chloride (0.099 ml, 1.367 mmol). The reaction wasstirred at 0° C. for 30 min. Example A2 (0.370 g, 1.301 mmol), DMF (4.00ml) and Et₃N (0.380 ml, 2.73 mmol) were added and the reaction wasstirred overnight with warming to R1. The reaction was quenched with 1MHCl (4 ml) and stirred for 15 min. The pH was adjusted back to 7 with50% NaOH and the mixture extracted with EtOAc (3×). The combinedorganics were washed with H₂O (1×) and brine (2×), dried (MgSO₄), andevaporated to afford a solid. The crude solid was triturated withCH₂Cl₂/hexanes. The remaining solids were collected by filtration,rinsed with hexanes and dried in vacuo to afford1-((3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)carbamoyl)cyclopropanecarboxylicacid (0.199 g, 39% yield) as cream-colored solid which was used withoutfurther purification. ¹H NMR (400 MHz, DMSO-d₆): δ 10.76 (s, 1H), 8.3(d, J=5.7 Hz, 1H), 8.26 (s, 1H), 7.96 (s, 1H), 7.84 (dd, J=2.4, 13 Hz,1H), 7.44-7.43 (m, 1H), 7.42-7.41 (m, 1H), 7.33 (s, 1H), 6.66-6.64 (m,1H), 3.84 (s, 3H), 1.39 (s, 4H); MS (ESI) m/z: 397.1 (M+H⁺).

Example B4

Thionyl chloride (1.09 mL, 15.0 mmol) was added slowly over 2 min to astirring solution of 1,1-cyclopropanedicarboxylic acid (1.95 g, 15.0mmol) and Et₃N (4.29 g, 42.4 mmol) in THF (15 mL) at 0° C. Aftercomplete addition, the reaction was further diluted with THF (25 mL) andthe reaction was stirred vigorously at 0° C. for 30 min. Thehydrochloride salt of Example A1 (4.00 g, 12.5 mmol) was added in threeportions and the resulting mixture was allowed to slowly warm to RT over4 h. The reaction mixture was concentrated to dryness in vacuo and theresidue was digested with aqueous MeOH. The remaining solids werecollected by filtration. This solid was dissolved in 1 M aq NaOH (30 mL)and methanol. The methanol was removed in vacuo, the remaining aqueousphase was diluted with water to a volume of 150 mL and extracted withEtOAc (3×50 mL). The combined EtOAc extracts were washed with sat aqNaHCO₃. The combined aqueous was acidified to pH 6 with 0.5 M HCl. Theresultant fine precipitate was collected by filtration, washed withacetonitrile (20 mL) and dried in vacuo to provide1-((2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)carbamoyl)cyclopropanecarboxylicacid (1.177 g). The remaining aqueous was concentrated in vacuo to about⅓ volume and the pH was reduced to pH 5 with 1 M aq HCl. The additionalprecipitate that formed was collected by filtration, washed withacetonitrile and dried in vacuo to provide an additional crop (1.34 g)of1-((2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)carbamoyl)cyclopropanecarboxylicacid (2.517 g total, 51% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 13.51 (brs, 1H), 11.30 (s, 1H), 8.37 (d, J=5.7 Hz, 1H), 8.25 (s, 1H), 8.19 (t,J=9.0 Hz, 1H), 7.95 (s, 1H), 7.28 (dd, J=11.6, 2.7 Hz, 1H), 7.22 (d,J=1.6 Hz, 1H), 7.01 (m, 1H), 6.69 (dd, J=5.6, 2.3 Hz, 1H), 3.84 (s, 3H),1.58-1.51 (m, 4H); MS (ESI) m/z: 397.1 (M+H⁺).

Example B5

To a solution of Example A12 (9.66 g, 32.0 mmol) in DMF (100 mL) wereadded cyclopropane-1,1-dicarboxylic acid monomethyl ester (6.91 g, 47.9mmol), TBTU (15.39 g, 47.9 mmol) and DIPEA (27.9 mL, 160 mmol). Thesides of the flask were rinsed with DMF (10 mL) and the resultantreaction mixture was stirred at RT overnight. The solvent was removedunder high vacuum and the residue was dissolved in EtOAc (600 mL). Theorganic phase was washed with water (100 mL), sat. aq. NaHCO₃ (200 mL)and brine (50 mL), dried (MgSO₄), and was concentrated in vacuo andpurified by silica gel chromatography (CH₂Cl₂-MeOH) to provide methyl1-((2,5-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)carbamoyl)cyclopropanecarboxylate(10.1 g, 69% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 10.94 (s, 1H), 8.39(d, J=5.7 Hz, 1H), 8.29 (s, 1H), 8.19 (dd, J=12.2, 7.2 Hz, 1H), 7.99 (s,1H), 7.59 (dd, J=11.0, 7.4 Hz, 1H), 7.26 (d, J=2.6 Hz, 1H), 6.73 (dd,J=5.6, 2.5 Hz, 1H), 3.86 (s, 3H), 3.70 (s, 3H), 1.61-1.54 (m, 4H); MS(ESI): m/z 429.1 [M+1]⁺.

To a suspension of methyl1-((2,5-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)carbamoyl)cyclopropanecarboxylate(5.8 g, 13.54 mmol) in THF (100 mL) were added water (50.0 mL) andlithium hydroxide monohydrate (2.84 g, 67.7 mmol). The reaction mixturewas stirred at RT for 40 minutes. The layers were separated and theorganic phase washed with brine (50 mL), dried (MgSO₄) and concentratedto dryness to afford lithium1-((2,5-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)carbamoyl)cyclopropanecarboxylate(5.11 g, 86% yield) as an off-white foam. MS (ESI): m/z 415.1 [M+1]⁺.

Example 1

Example B1 (0.060 g, 0.269 mmol), Example A3 (0.060 g, 0.198 mmol), TBTU(0.129 g, 0.403 mmol) and i-Pr₂NEt (0.089 ml, 0.538 mmol) were combinedin DMF (2 mL). The resultant mixture was stirred overnight at RT. Anadditional portion of Example B1 (60 mg), TBTU (120 mg) and i-Pr₂NEt(0.080 mL) was added and the mixture was stirred an additional 24 h. Thereaction mixture was partitioned between water and EtOAc. The organiclayer was washed with 5% aq LiCl, dried (MgSO₄), concentrated in vacuoand purified by chromatography on silica gel and reverse-phase silicagel to provideN-(2,3-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(21 mg, 15% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 10.82 (s, 1H), 9.89 (s,1H), 8.38 (d, J=5.5 Hz, 1H), 8.27 (s, 1H), 7.97 (s, 1H), 7.76 (m, 1H),7.61-7.57 (m, 2H), 7.29 (d, J=2.5 Hz, 1H), 7.22-7.13 (m, 3H), 6.71 (m,1H), 3.84 (s, 3H), 1.61 (m, 2H), 1.55 (m, 2H); MS (ESI) m/z: 508.1(M+H⁺).

Example 2

Example B1 (51 mg, 0.229 mmol), Example A2 (50 mg, 0.176 mmol), TBTU (85mg, 0.264 mmol) and DIEA (35 μl, 0.212 mmol) were combined in DMF (1 mL)and stirred overnight at RT. The reaction mixture was diluted with EtOAc(20 mL) and washed with water, satd aq NaHCO₃, and brine. The organicswere dried (MgSO₄), concentrated in vacuo and was purified via silicagel chromatography to provideN-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(65 mg, 76% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 10.35 (s, 1H), 9.97 (s,1H), 8.35 (d, J=5.7 Hz, 1H), 8.25 (s, 1H), 7.95 (s, 1H), 7.85 (dd,J=13.2, 2.2 Hz, 1H), 7.64-7.60 (m, 2H), 7.46 (m, 1H), 7.32 (t, J=9.0 Hz,1H), 7.22 (d, J=2.5 Hz, 1H), 7.12 (m, 2H), 6.60 (dd, J=5.7, 2.4 Hz, 1H),3.84 (s, 3H), 1.46 (m, 2H), 1.43 (m, 2H); MS (ESI) m/z: 490.1 (M+H⁺).

Example 3

Example B2 (60% purity, 0.15 g, 0.22 mmol), benzylamine (0.036 ml, 0.326mmol), EDC (0.062 g, 0.326 mmol), HOBT (0.050 g, 0.326 mmol) and Et₃N(0.091 ml, 0.652 mmol) were combined in DMF (2.5 ml) and stirred at RT.Additional benzyl amine (10 mg) was added and then the reaction wasstirred overnight at RT. The completed reaction was poured into waterand extracted with EtOAc (3×). The combined organic layers were washedwith NaHCO₃, LiCl, brine, dried (Na₂SO₄) and purified by silica gelcolumn chromatography (EtOAc/hexane→MeOH/CH₂Cl₂) to obtainN-benzyl-N′-(2,3-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)cyclopropane-1,1-dicarboxamide(22 mg, 20% yield) following lyophilation. ¹H NMR (400 MHz, DMSO-d₆): δ11.9 (s, 1H), 8.45 (t, J=5.6 Hz, 1H), 8.38 (m, 1H), 8.26 (s, 1H), 7.96(m, 2H), 7.1-7.4 (m, 7H), 6.73 (dd, J=5.2, 2.4 Hz, 1H), 4.32 (d, J=5.6Hz, 2H), 3.84 (s, 3H), 1.55 (s, 4H); MS (ESI) m/z: 504.1 (M+H⁺).

Example 4

Benzylamine (0.017 ml, 0.151 mmol), Example B3 (0.040 g, 0.101 mmol) andi-Pr₂NEt (0.025 ml, 0.151 mmol) were combined in DMF (0.4 mL). TBTU(0.049 g, 0.151 mmol) was added and the mixture was stirred at RTovernight. The completed reaction was diluted with EtOAc (30 mL), washedwith H₂O (15 mL), 5% citric acid (15 mL) and saturated brine, dried(MgSO₄), concentrated in vacuo and purified by chromatography to affordN-benzyl-N′-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)cyclopropane-1,1-dicarboxamide(0.028 g, 57% yield). It was converted to the corresponding HCl salt byreacting with HCl (4.0 M HCl in dioxane, 1.0 eq.). ¹H NMR (DMSO-d₆): δ10.97 (s, 1H), 8.55-8.44 (m, 3H), 8.23 (s, 1H), 7.90 (dd, J=13.6, 1.6Hz, 1H), 7.59 (s, 1H), 7.50-7.38 (m, 2H), 7.31-7.19 (m, 5H), 6.98 (s,1H), 4.31 (d, J=6.0 Hz, 2H), 3.89 (s, 3H), 1.40-1.39 (m, 4H); MS (ESI)m/z: 486.2 (M+H⁺).

Example 5

Using a procedure analogous to Example 4, aniline (0.015 ml, 0.159 mmol)and Example B3 (0.042 g, 0.106 mmol) were combined to provideN-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-phenylcyclopropane-1,1-dicarboxamide(0.040 g, 79% yield) as a light yellow oil. It was converted to thecorresponding HCl salt by reacting with HCl (4.0 M HCl in dioxane, 1.0eq.). ¹H NMR (DMSO-d₆): δ 10.43 (s, 1H), 9.96 (s, 1H), 8.52-8.49 (m,2H), 8.21 (s, 1H), 7.92 (d, J=11.2 Hz, 1H), 7.64-7.52 (m, 4H), 7.42 (t,J=8.8 Hz, 1H), 7.34-7.30 (m, 2H), 7.08 (t, J=6.8 Hz, 1H), 6.95 (s, 1H),3.91 (s, 3H), 1.50-1.44 (m, 4H); MS (ESI) m/z: 472.1 (M+H⁺).

Example 6

Using a procedure analogous to Example 4, Example B3 (0.042 g, 0.106mmol) and 3-aminobenzotrifluoride (0.020 ml, 0.159 mmol) were combinedto provideN-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(3-(trifluoromethyl)phenyl)cyclopropane-1,1-dicarboxamide(0.018 g, 32% yield) as a light yellow oil. It was converted to thecorresponding HCl salt by reacting with HCl (4.0 M HCl in dioxane, 1.0eq.). ¹H NMR (DMSO-d₆): δ 10.39 (s, 1H), 10.28 (s, 1H), 8.52-8.46 (m,2H), 8.18 (s, 1H), 8.15 (s, 1H), 7.58-7.49 (m, 3H), 7.44-7.38 (m, 2H),6.93 (s, 1H), 3.91 (s, 3H), 1.50-1.42 (m, 4H); MS (ESI) m/z: 540.1(M+H⁺).

Example 7

Example B4 (1.19 g, 3.00 mmol), 4-fluoroaniline (0.367 g, 3.30 mmol),and DIEA (0.54 ml, 3.27 mmol) were combined in DMF (10.5 mL). TBTU (1.25g, 3.89 mmol) was added and the resultant solution was stirred at RT.After 36 h, the reaction mixture was diluted with EtOAc (150 mL) andwashed with water (50 mL), brine (2×50 mL), satd sodium bicarbonatesolution (2×50 mL) and brine (50 mL). The combined aqueous phases wereback extracted with EtOAc (50 mL). The combined organics were dried(Na₂SO₄) and concentrated to a viscous oil. The residue was completelydissolved in acetonitrile (15 mL) and the solution was sonicated untilprecipitation occurred. The fine suspension was allowed to standovernight, and collected by filtration, washed with acetonitrile (25mL), and dried in vacuo to provideN-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(1.258 g). The filtrate was concentrated to about a 3 mL volume toafford a second crop (0.106 g, 92% total yield). NMR (400 MHz, DMSO-d₆):δ 10.62 (s, 1H), 9.91 (s, 1H), 8.38 (d, J=4.9 Hz, 1H), 8.25 (s, 1H),7.96-7.90 (m, 2H), 7.60-7.56 (m, 2H), 7.26-7.23 (m, 2H), 7.15 (In, 2H),7.01 (m, 1H), 6.67 (m, 1H), 3.84 (s, 3H), 1.60 (m, 2H), 1.54 (m, 2H); MS(ESI) m/z: 490.2 (M+H⁺).

Example 8

4-Methoxyaniline (0.020 g, 0.159 mmol) and Example B3 (0.042 g, 0.106mmol) were combined using a procedure analogous to Example 4 to provideN-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(4-methoxyphenyl)cyclopropane-1,1-dicarboxamide(0.019 g, 36% yield). ¹H NMR (DMSO-d₆): δ 10.41 (s, 1H), 9.76 (s, 1H),8.35 (dd, J=6.0, 1.2 Hz, 1H), 8.24 (s, 1H), 7.95 (s, 1H), 7.85 (d,J=13.2 Hz, 1H), 7.50-7.44 (m, 3H), 7.32 (t, J=8.8 Hz, 1H), 7.22 (s, 1H),6.86 (dd, J=9.2, 1.6 Hz, 2H), 6.60 (m, 1H), 3.84 (s, 3H), 3.70 (s, 3H),1.50-1.42 (m, 4H); MS (ESI) m/z: 502.1 (M+H⁺).

Example 9

m-Anisidine (0.020 g, 0.159 mmol) and Example B3 (0.042 g, 0.106 mmol)were combined using a procedure analogous to Example 4 to provideN-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(3-methoxyphenyl)cyclopropane-1,1-dicarboxamide(0.031 g, 58% yield) as a colorless oil. It was converted to thecorresponding HCl salt by reacting with HCl (4.0 M HCl in dioxane, 1.0eq.). ¹H NMR (DMSO-d₆): δ 10.42 (s, 1H), 9.92 (s, 1H), 8.68 (d, J=2.4Hz, 1H), 8.60 (d, J=6.8 Hz, 1H), 8.34 (d, J=3.6 Hz, 1H), 7.93 (dd,J=12.8, 1.6 Hz, 1H), 7.80 (d, J=2.8 Hz, 1H), 7.55-7.52 (m, 1H), 7.44 (t,J=8.8 Hz, 1H), 7.31 (s, 1H), 7.20-7.16 (m, 3H), 6.63 (m, 1H), 3.92 (s,3H), 3.70 (s, 3H), 1.50-1.41 (m, 4H); MS (ESI) m/z: 502.2 (M+H⁺).

Example 10

3-Fluoroaniline (0.018 g, 0.159 mmol) and Example B3 (0.042 g, 0.106mmol) were combined using a procedure analogous to Example 4 to provideN-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(3-fluorophenyl)cyclopropane-1,1-dicarboxamide(0.022 g, 42% yield). ¹H NMR (DMSO-d₆): δ 10.27 (s, 1H), 10.17 (s, 1H),8.35 (d, J=5.6 Hz, 1H), 8.25 (s, 1H), 7.95 (s, 1H), 7.84 (dd, J=13.2,2.4 Hz, 1H), 7.62 (d, J=12.0 Hz, 1H), 7.46 (d, J=8.8, 1.6 Hz, 1H),7.38-7.29 (m, 3H), 7.22 (d, J=2.0 Hz, 1H), 6.89 (t, J=8.0 Hz, 1H), 6.60(dd, J=5.6, 2.0 Hz, 1H), 3.84 (s, 3H), 1.47-1.42 (m, 4H); MS (ESI) m/z:490.1 (M+H⁺).

Example 11

Example B1 (53 mg, 0.237 mmol), Example A4 (51 mg, 0.182 mmol), TBTU (88mg, 0.273 mmol) and i-Pr₂NEt (0.045 mL, 0.272 mmol) were combined in DMF(1 mL) using a procedure analogous to Example 2 to affordN-(4-fluorophenyl)-N′-(3-methyl-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)cyclopropane-1,1-dicarboxamide(70 mg, 80% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 10.12 (s, 1H), 10.00(s, 1H), 8.31 (d, J=6.0 Hz, 1H), 8.22 (s, 1H), 7.92 (s, 1H), 7.64-7.60(m, 3H), 7.54 (m, 1H), 7.16-7.11 (m, 3H), 7.04 (d, J=8.8 Hz, 1H), 6.46(dd, J=5.6, 2.4 Hz, 1H), 3.84 (s, 3H), 2.08 (s, 3H), 1.45 (m, 4H); MS(ESI) m/z: 486.2 (M+H⁺).

Example 12

A solution of 2-(4-fluorophenyl)acetyl chloride (0.173 g, 1.0 mmol) indry ether (1.0 mL) was slowly added to a suspension of silver cyanate(0.180 g, 1.2 mmol) in ether (1.5 mL). The mixture was subsequentlyrefluxed for 2 h under N₂. After filtration of the silver salts, solventwas removed under reduced pressure and the residue was dissolved inCH₂Cl₂ (4.0 mL).

A portion of the above solution (0.179 g, 1.0 mmol) and Example A2(0.071 g, 0.25 mmol) were combined in CH₂Cl₂ (2.0 mL). After stirring atRT overnight, the reaction was concentrated in vacuo and purified bychromatography to afford1-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)ureafluorophenyl)acetyl)urea (0.020 g, 17% yield) as a white solid. ¹H NMR(DMSO-d₆): δ 11.03 (s, 1H), 10.57 (s, 1H), 8.35 (d, J=5.6 Hz, 1H), 8.24(s, 1H), 7.95 (s, 1H), 7.76 (dd, J=12.8, 2.4 Hz, 1H), 7.37-7.32 (m, 4H),7.20-7.13 (m, 3H), 6.61 (dd, J=5.6, 2.4 Hz, 1H), 3.84 (s, 3H), 3.73 (s,2H); MS (ESI) m/z: 464.1 (M+H⁺).

Example 13

To a solution of 4-aminopyridine (0.019 g, 0.202 mmol) in CH₂Cl₂ (5 ml)was added Example B3 (0.040 g, 0.101 mmol), TBTU (0.039 g, 0.151 mmol)and triethylamine (0.020 g, 0.202 mmol). The reaction mixture wasstirred at RT for 13 hours, washed with water, the organic layer wasconcentrated and purified by chromatography (THF/acetonitrile) toprovideN-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(pyridin-4-yl)cyclopropane-1,1-dicarboxamide(0.032 g, 67% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ10.45 (s, 1H), 10.25 (s, 1H), 8.42 (d, J=6 Hz, 2H), 8.35 (d, J=6 Hz,1H), 8.25 (s, 1H), 7.95 (s, 1H), 7.82 (m, 1H), 7.65 (d, J=6 Hz, 2H),7.44 (m, 1H), 7.32 (m, 1H), 7.20 (d, J=2.4 Hz, 1H), 6.60 (m, 1H), 3.85(s, 3H), 1.47 (s, 4H); MS (ESI) m/z: 473.1 (M+H⁺).

Example 14

Using a procedure analogous to Example 13, 3-aminopyridine (0.019 g,0.202 mmol), Example B3 (0.040 g, 0.101 mmol), TBTU (0.039 g, 0.151mmol) and triethylamine (0.020 g, 0.202 mmol) were combined in CH₂Cl₂ (5ml) to provideN-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(pyridin-3-yl)cyclopropane-1,1-dicarboxamide(0.032 g, 67% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ10.36 (s, 1H), 10.16 (s, 1H), 8.78 (d, J=2.5 Hz, 1H), 8.35 (d, J=6 Hz,1H), 8.25 (m, 2H), 8.00 (m, 1H), 7.94 (s, 1H), 7.84 (m, 1H), 7.44 (m,1H), 7.33 (m, 2H), 7.22 (d, J=2.5 Hz, 1H), 6.60 (m, 1H), 3.85 (s, 3H),1.47 (s, 4H); MS (ESI) m/z: 473.1 (M+H⁺).

Example 15

To a solution of 3-chlorobenzylamine (0.029 g, 0.202 mmol) in CH₂Cl₂ (3ml) was added Example B3 (0.040 g, 0.101 mmol), TBTU (0.039 g, 0.151mmol) and triethylamine (0.020 g, 0.202 mmol). The reaction mixture wasstirred at RT for 13 hours. The reaction mixture was washed withsaturated NaHCO₃ and brine, dried and the solvent evaporated to provideN-(3-chlorobenzyl)-N′-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)cyclopropane-1,1-dicarboxamide(0.036 g, 69% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ10.80 (s, 1H), 8.49 (m, 2H), 8.35 (d, J=6 Hz, 1H), 8.25 (s, 1H), 7.95(s, 1H), 7.82 (m, 2H), 7.55-7.18 (m, 5H), 6.60 (m, 1H), 4.31 (d, J=6 Hz,2H), 3.85 (s, 3H), 1.38 (s, 4H); MS (ESI) m/z: 520.2 (M+H⁺).

Example 16

To a solution of (S)-(−)-alpha-methylbenzylamine (0.024 g, 0.202 mmol)in CH₂Cl₂ (3 ml) was added Example B3 (0.040 g, 0.101 mmol), TBTU (0.039g, 0.151 mmol) and triethylamine (10.21 mg, 0.101 mmol). The reactionmixture was stirred at RT for 13 hours. The reaction mixture was washedwith saturated NaHCO₃ and brine, dried, concentrated in vacuo andrecrystalled (acetonitrile) to provideN-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-((S)-1-phenylethyl)cyclopropane-1,1-dicarboxamide(0.04 g, 79% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.72(s, 1H), 8.34 (d, J=5.5 Hz, 1H), 8.31 (d, J=8 Hz, 1H), 8.25 (s, 1H),7.95 (s, 1H), 7.82 (m, 1H), 7.42 (m, 1H), 7.29 (m, 5H), 7.19 (m, 2H),6.60 (m, 1H), 4.99 (m, 1H), 3.85 (s, 3H), 1.40 (m, 7H); MS (ESI) m/z:500.2 (M+H⁺).

Example 17

Using a procedure analogous to Example 16,(R)-(+)-alpha-methylbenzylamine (0.024 g, 0.202 mmol), Example B3 (0.040g, 0.101 mmol), TBTU (0.039 g, 0.151 mmol) and triethylamine (0.020 g,0.202 mmol) were combined in CH₂Cl₂ (3 ml) and the crude material wasrecrystallized (methanol) to provideN-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-((R)-1-phenylethyl)cyclopropane-1,1-dicarboxamide(0.040 g, 79% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ10.72 (s, 1H), 8.34 (d, J=5.5 Hz, 1H), 8.31 (d, J=8 Hz, 1H), 8.25 (s,1H), 7.95 (s, 1H), 7.82 (m, 1H), 7.42 (m, 1H), 7.29 (m, 5H), 7.19 (m,2H), 6.60 (m, 1H), 4.99 (m, 1H), 3.85 (s, 3H), 1.40 (m, 7H); MS (ESI)m/z: 500.1 (M+H⁺).

Example 18

To a solution of 4-fluorobenzylamine (0.019 g, 0.151 mmol) in CH₂Cl₂ wasadded Example B3 (0.030 g, 0.076 mmol), TBTU (0.039 g, 0.151 mmol) andtriethylamine (0.015 g, 0.151 mmol). The reaction mixture was stirred atRT for 3 hours. The reaction mixture was washed with saturated sodiumbicarbonate and brine, dried, concentrated in vacuo and the residue wasrecrystallized (methanol) to provideN-(4-fluorobenzyl)-N′-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)cyclopropane-1,1-dicarboxamide(0.025 g, 66% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ10.83 (s, 1H), 8.40 (t, J=5.5 Hz, 1H), 8.34 (d, J=5.5 Hz, 1H), 8.25 (s,1H), 7.95 (s, 1H), 7.82 (m, 1H), 7.43 (m, 1H), 7.30 (m, 3H), 7.20 (d,J=2.5 Hz, 1H), 7.12 (m, 2H), 6.59 (m, 1H), 4.32 (d, J=6 Hz, 2H), 3.85(s, 3H), 1.40 (s, 4H); MS (ESI) m/z: 504.1 (M+H⁺).

Example 19

Example 31 (0.061 g, 0.128 mmol), K₂CO₃ (0.053 g, 0.385 mmol) andiodoethane (0.060 g, 0.385 mmol) were combined in DMSO (1 mL) and themixture was stirred at RT for 24 h. The reaction mixture was poured intoEtOAc (20 mL) and water (30 mL). The layers were separated and theaqueous layer was extracted with EtOAc (15 mL). The combined organicswere washed with brine, dried (Na₂SO₄), concentrated and purified bysilica gel chromatography (EtOAc-hexanes) to affordN-(4-(2-(1-ethyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(37 mg; 57% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.35(s, 1H), 9.97 (s, 1H), 8.35 (d, J=6.0 Hz, 1H), 8.23 (s, 1H), 7.96 (s,1H), 7.85 (dd, J=13.2 Hz, 2.0 Hz, 1H), 7.63-7.60 (m, 2H), 7.45 (dd,J=8.8 Hz, 1.6 Hz, 1H), 7.31 (t, J=8.8 Hz, 1H), 7.23 (d, J=2.0 Hz, 1H),7.15-7.11 (m, 2H), 6.59 (dd, J=5.6 Hz, 2.4 Hz, 1H), 4.13 (q, J=7.2 Hz,2H), 1.45-1.42 (m, 4H), 1.37 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 504.1(M+H⁺).

Example 20

Using a procedure analogous to Example 19, Example 31 (0.061 g, 0.128mmol), K₂CO₃ (0.053 g, 0.385 mmol) and 1-iodopropane (0.11 g, 0.64 mmol)were combined to affordN-(3-fluoro-4-(2-(1-propyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a white solid. (51 mg, 77% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 10.35(s, 1H), 9.97 (s, 1H), 8.35 (d, J=5.6 Hz, 1H), 8.28 (s, 1H), 7.96 (s,1H), 7.84 (dd, J=13.2 Hz, 2.0 Hz, 1H), 7.63-7.60 (m, 2H), 7.46 (dd,J=8.8 Hz, 1.2 Hz, 1H), 7.31 (t, J=8.8 Hz, 1H), 7.23 (d, J=2.0 Hz, 1H),7.15-7.11 (m, 2H), 6.59 (dd, J=5.6 Hz, 2.4 Hz, 1H), 4.06 (t, J=6.8 Hz,2H), 1.82-1.73 (m, 2H), 1.47-1.41 (m, 4H), 0.80 (t, J=7.2 Hz, 3H); MS(ESI) m/z: 518.2 (M+H⁺).

Example 21

Using a procedure analogous to Example 19, Example 31 (0.091 g, 0.19mmol), K₂CO₃ (0.08 g, 0.57 mmol) and ethyl 2-bromoacetate (0.16 g, 0.96mmol) were combined to affordN-(3-fluoro-4-(2-(1-(1-ethoxy-2-acetyl)-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(97 mg, 90% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.35(s, 1H), 9.97 (s, 1H), 8.37 (d, J=5.6 Hz, 1H), 8.29 (s, 1H), 8.02 (s,1H), 7.85 (dd, J=13.2 Hz, 2.0 Hz, 1H), 7.63-7.60 (m, 2H), 7.47-7.45 (m,1H), 7.32 (1, J=8.8 Hz, 1H), 7.23 (d, J=2.8 Hz, 1H), 7.15-7.11 (m, 2H),6.64 (dd, J=6.0 Hz, 2.4 Hz, 1H), 5.07 (s, 2H), 4.14 (q, J=7.2 Hz, 2H),1.45-1.42 (m, 4H), 1.19 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 562.1 (M+H⁺).

To a solution ofN-(3-fluoro-4-(2-(1-(1-ethoxy-2-acetyl)-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(0.097 g, 0.173 mmol) in THF (4 mL) was added LiAlH₄ (2 M in THF, 0.173ml, 0.345 mmol) at −78° C. The mixture was warmed to RT and stirred for1 h. It was cooled to 0° C., methanol (0.2 ml) and sat. aq Na₂SO₄solution (0.2 ml) were added and the mixture stirred for 4 h at RT. Themixture was filtered through a Celite® pad, and the pad was washed withTHF (2×2 mL). The combined filtrate was concentrated to afford crudeproduct which was purified by silica gel chromatography (CH₂Cl₂-MeOH) toaffordN-(3-fluoro-4-(2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.(41 mg, 46% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 10.35 (s, 1H), 9.97 (s,1H), 8.35 (d, J=4.8 Hz, 1H), 8.26 (s, 1H), 7.98 (s, 1H), 7.85 (dd,J=13.2 Hz, 2.4 Hz, 1H), 7.63-7.60 (m, 2H), 7.47-7.44 (m, 1H), 7.32 (t,J=9.2 Hz, 1H), 7.24 (d, J=1.6 Hz, 1H), 7.15-7.11 (m, 2H), 6.62-6.60 (m,1H), 4.85 (brs, 1H), 4.14 (t, J=5.2 Hz, 2H), 3.72 (t, J=5.2 Hz, 2H),1.47-1.41 (m, 4H); MS (ESI) m/z: 520.1 (M+H⁺).

Example 22

Using a procedure analogous to Example 15, 4-chloroaniline (0.064 g,0.505 mmol) in CH₂Cl₂ (5 mL), Example B4, (0.100 g, 0.252 mmol), TBTU(0.096 g, 0.378 mmol) and triethylamine (0.051 g, 0.505 mmol) werecombined and purified by silica gel chromatography (EtOAc/CH₂Cl₂) toprovideN-(4-chlorophenyl)-N′-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)cyclopropane-1,1-dicarboxamide(0.138 mmol, 55% yield) as a white solid. NMR (400 MHz, DMSO-d₆): δ10.48 (s, 1H), 10.00 (s, 1H), 8.40 (d, J=5.5 Hz, 1H), 8.25 (s, 1H), 7.95(s, 1H), 7.90 (m, 1H), 7.62 (d, J=9 Hz, 2H), 7.37 (d, J=9 Hz, 2H), 7.25(m, 2H), 7.0 (m, 1H), 6.66 (m, 1H), 3.85 (s, 3H), 1.54 (m, 4H); MS (ESI)m/z: 506.2 (M+H⁺).

Example 23

Using a procedure analogous to Example 15, Example B4 (0.100 g, 0.252mmol), TBTU (0.071 g, 0.278 mmol), triethylamine (0.051 g, 0.505 mmol)and p-toluidine (0.054 g, 0.505 mmol) were combined and purified bysilica gel chromatography to provideN-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-p-tolylcyclopropane-1,1-dicarboxamide(0.070 g, 57% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ10.68 (s, 1H), 9.79 (s, 1H), 8.40 (d, J=5.5 Hz, 1H), 8.25 (s, 1H), 7.95(m, 2H), 7.43 (d, J=8 Hz, 2H), 7.22 (m, 2H), 7.11 (d, J=8 Hz, 2H), 7.02(m, 1H), 6.67 (m, 1H), 3.85 (s, 3H), 2.24 (s, 3H), 1.57 (m, 4H); MS(ESI) m/z: 486.2 (M+H⁺).

Example 24

Using a procedure analogous to Example 15, 3,4-difluoroaniline (0.065 g,0.505 mmol), Example B4 (0.100 g, 0.252 mmol), TBTU (0.071 g, 0.278mmol) and triethylamine (0.051 g, 0.505 mmol) were combined and purifiedby silica gel chromatography to provideN-(3,4-difluorophenyl)-N′-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)cyclopropane-1,1-dicarboxamide(0.06 g, 47% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 10.48 (s, 1H), 10.22(s, 1H), 8.46 (d, J=5.5 Hz, 1H), 8.33 (s, 1H), 7.99 (s, 1H), 7.95 (m,1H), 7.84 (m, 1H), 7.40 (m, 2H), 7.35 (m, 2H), 7.10 (m, 1H), 6.74 (m,1H), 3.95 (s, 3H), 1.61 (m, 4H); MS (ESI) m/z: 508.2 (M+H⁺).

Example 25

4-Trifluoroaniline (0.081 g, 0.505 mmol), Example B4 (0.100 g, 0.252mmol), TBTU (0.071 g, 0.278 mmol) and triethylamine (0.051 g, 0.505mmol) were combined using a procedure analogous to Example 15 to provideN-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(4-(trifluoromethyl)phenyl)cyclopropane-1,1-dicarboxamide(0.028 g, 21% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 10.33 (s, 1H), 10.31(s, 1H), 8.40 (d, J=5.5 Hz, 1H), 8.25 (s, 1H), 7.95 (s, 1H), 7.82 (m,3H), 7.67 (m, 2H), 7.25 (m, 2H), 7.02 (m, 1H), 6.66 (m, 1H), 3.85 (s,3H), 1.53 (m, 4H); MS (ESI) m/z: 540.2 (M+H^(+).)

Example 26

Example B4 (0.050 g, 0.126 mmol), N,N-diisopropylethylamine (0.016 g,0.126 mmol), 5-amino-2-fluorobenzonitrile (0.017 g, 0.126 mmol), andBOP-chloride (0.032 g, 0.126 mmol) were combined in CH₂Cl₂ (5 mL) usinga procedure analogous to Example 28 to provideN-(3-cyano-4-fluorophenyl)-N′-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)cyclopropane-1,1-dicarboxamide(0.030 g, 47% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 10.38 (s, 1H), 10.27(s, 1H), 8.40 (d, J=5.5 Hz, 1H), 8.25 (s, 1H), 8.11 (m, 1H), 7.95 (s,1H), 7.88 (m, 2H), 7.50 (m, 1H), 7.25 (m, 2H), 7.02 (d, J=10 Hz, 1H),6.89 (m, 1H), 3.85 (s, 3H), 1.55 (m, 4H); MS (ESI) m/z: 515.2 (M+H⁺).

Example 27

Example B4 (0.100 g, 0.252 mmol), N,N-diisopropylethylamine (0.033 g,0.252 mmol), 2,4-difluoroaniline (0.065 g, 0.505 mmol), and BOP-chloride(0.064 g, 0.252 mmol) were combined in CH₂Cl₂ (5 mL) using a procedureanalogous to Example 28 to provideN-(2,4-difluorophenyl)-N′-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)cyclopropane-1,1-dicarboxamide(0.034 g, 27% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 10.59 (s, 1H), 10.23(s, 1H), 8.40 (d, J=5.5 Hz, 1H), 8.25 (s, 1H), 7.95 (s, 1H), 7.89 (m,1H), 7.71 (m, 1H), 7.35 (m, 1H), 7.26 (m, 2H), 7.02 (m, 2H), 6.68 (m,1H), 3.85 (s, 3H), 1.66 (m, 4H); MS (ESI) m/z: 508.2 (M+H⁺).

Example 28

To a solution of 4-aminobenzonitrile (0.089 g, 0.757 mmol) in CH₂Cl₂ (5mL) was added Example B4 (0.150 g, 0.378 mmol), BOP-chloride (0.096 g,0.378 mmol) and diisopropylethyl amine (0.098 g, 0.757 mmol). Thereaction mixture was stirred at RT for 13 hours. The solvent from thereaction mixture was completely removed and the residue was purified byflash chromatography to provideN-(4-cyanophenyl)-N′-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)cyclopropane-1,1-dicarboxamide(0.075 g, 40% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 10.38 (s, 1H), 10.15(s, 1H), 8.33 (d, J=5.5 Hz, 1H), 8.20 (s, 1H), 7.90 (s, 1H), 7.75 (m,4H), 7.20 (m, 3H), 6.96 (m, 1H), 6.62 (m, 1H), 3.85 (m 3H), 1.50 (m,4H); MS (ESI) m/z: 497.2 (M+H⁺).

Example 29

2-Chloro-4-fluoroaniline (0.073 g, 0.505 mmol), Example B4 (0.100 g,0.252 mmol), BOP-chloride (0.064 g, 0.252 mmol) anddiisopropylethylamine (0.065 g, 0.505 mmol) were combined in CH₂Cl₂ (5mL) using a procedure analogous to Example 28 to provideN-(2-chloro-4-fluorophenyl)-N′-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)cyclopropane-1,1-dicarboxamide(0.055 g, 42% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 10.53 (s, 1H), 10.48(s, 1H), 8.40 (d, J=5.5 Hz, 1H), 8.25 (s, 1H), 7.95 (s, 1H), 7.82 (m,2H), 7.50 (m, 1H), 7.25 (m, 3H), 7.02 (d, J=10 Hz, 1H), 6.89 (m, 1H),3.85 (s, 3H), 1.70 (m, 4H); MS (ESI) m/z: 524.2 (M+H⁺).

Example 30

Example B1 (80 mg, 0.36 mmol), Example A5 (108 mg, 0.36 mmol), i-Pr₂NEt(0.1 mL, 0.54 mmol) and TBTU (180 mg, 0.54 mmol) were combined in DMF (3mL) and the mixture was stirred overnight at RT. Water was added andresultant precipitate was collected by filtration. The solid wasdissolved in EtOAc and the organic layer was dried (Na₂SO₄),concentrated in vacuo and purified by silica gel chromatography(EtOAc-hexanes). The pure fractions were combined and concentrated invacuo and the residue was precipitated from EtOAc-hexanes. The resultantsolid was collected by filtration and dried under vacuum to obtainN-(3-chloro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(95 mg, 52% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 10.3 (s, 1H), 9.99 (s,1H), 8.34 (d, J=5.6 Hz, 1H), 8.25 (s, 1H), 8.04 (d, J=2.4 Hz, 1H), 7.95(s, 1H), 7.62 (m, 3H), 7.32 (d, J=8.8 Hz, 1H), 7.20 (d, J=2.8 Hz, 1H),7.11 (m, 2H), 6.52 (dd, J=5.6, 2.4, Hz, 1H), 3.89 (s, 3H), 1.44 (m, 4H);MS (ESI) m/z: 506.1 (M+H⁺).

Example 31

To a solution of Example A6 (0.242 g, 0.896 mmol) in DMF (3 ml) wasadded Example B1 (0.20 g, 0.896 mmol), EDC (0.258 g, 1.344 mmol), andHOBt (0.206 g, 1.344 mmol). The mixture was stirred at RT for 3 hours.Water was added and the solution was extracted with EtOAc (3×). Theorganic extracts were washed with brine, dried (Na₂SO₄), concentrated invacuo and purified by silica gel column chromatography (EtOAc/hexane).Pure fractions containing product were combined and concentrated. Theresidue was treated with EtOAc/hexane and the resultant precipitate wascollected by filtration and dried under vacuum to obtainN-(4-(2-(1H-pyrazol-4-yl)pyridin-4-yloxy)-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(0.205 g, 48% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 13.1 (br s, 1H), 10.4(s, 1H), 9.98 (s, 1H), 8.35 (d, J=5.2 Hz, 1H), 8.32 (brs, 1H), 8.02 (brs, 1H), 7.85 (dd, J=13.2, 2.4 Hz, 1H), 7.61 (m, 2H), 7.46 (m, 1H), 7.32(m, 2H), 7.13 (m, 2H), 6.58 (dd, J=6.6, 2.4 Hz, 1H), 1.44 (m, 4H); MS(ESI) m/z: 476.2 (M+H⁺).

Example 32

To a solution of Example B1 (0.100 g, 0.448 mmol) in CH₂Cl₂ (5 mL) wasadded Example A7 (0.134 g, 0.448 mmol), BOP-chloride (0.228 g, 0.896mmol) and diisopropylethylamine (0.116 g, 0.896 mmol). The reactionmixture was stirred at RT for 15 hours. The solvent from the reactionmixture was completely removed and the residue was recrystallized(acetonitrile) to provideN-(2-fluoro-3-methyl-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(0.060 g, 27% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 10.74 (s, 1H), 9.80(s, 1H), 8.40 (d, J=5.5 Hz, 1H), 8.25 (s, 1H), 7.95 (s, 1H), 7.82 (m,1H), 7.60 (m, 2H), 7.20 (m, 3H), 6.95 (d, J=10 Hz, 1H), 6.56 (m, 1H),3.83 (s, 3H), 2.00 (s, 3H), 1.65 (m, 4H); MS (ESI) m/z: 504.2 (M+H⁺).

Example 33

Example B3 (65 mg, 0.164 mmol), TBTU (79 mg, 0.246 mmol), DIEA (0.114ml, 0.656 mmol) and (S)-1-(4-fluorophenyl)ethylamine (27.4 mg, 0.197mmol) were combined in DMF (2 ml) and stirred at RT overnight. Thereaction was diluted with satd. NaHCO₃ and extracted with EtOAc (2×).The combined organics were washed with satd. LiCl (2×), dried (MgSO₄),concentrated in vacuo and purified by reverse phase C18 chromatography(MeCN (w/0.1% TFA)/H₂O (w/0.1% TFA)). Pure fractions were combined,treated with satd. NaHCO₃ (pH 8) and extracted with EtOAc (3×). Thecombined organics were washed with brine (1×), dried (MgSO₄), filteredand evaporated. The material was dissolved in MeCN/H₂O, treated with 0.1N HCl (1.14 ml, 0.114 mmol), frozen and lyophilized to affordN-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-((S)-1-(4-fluorophenyl)ethyl)cyclopropane-1,1-dicarboxamidehydrochloride (55 mg) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ10.78 (s, 1H), 8.48-8.47 (m, 2H), 8.29 (d, J=7.95 Hz, 1H), 8.16 (br s,1H), 7.90 (dd, J=2.0, 14 Hz, 1H), 7.54-7.32 (m, 5H), 7.14-7.1 (m, 2H),6.92 (br s, 1H), 5.04-4.97 (m, 1 II), 3.89 (s, 3H), 1.41-1.36 (m, 7H);MS (ESI) m/z: 518.2 (M+H⁺).

Example 34

Using a procedure analogous to Example 33, Example B3 (65 mg, 0.164mmol), TBTU (79 mg, 0.246 mmol), DIEA (0.114 ml, 0.656 mmol) and(1S)-1-(4-fluorophenyl)propylamine hydrochloride (37.3 mg, 0.197 mmol)were combined in DMF (2 ml) to provideN-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-M-((S)-1-(4-fluorophenyl)propyl)cyclopropane-1,1-dicarboxamide.It was further reacted with 0.1 N HCl (0.94 ml, 1.0 eq) to provideN-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-((S)-1-(4-fluorophenyl)propyl)cyclopropane-1,1-dicarboxamidehydrochloride (49 mg) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆):δ 10.8 (s, 1H), 8.49-8.47 (m, 2H), 8.26 (d, J=8.4 Hz, 1H), 8.2 (br s,1H), 7.88 (dd, J=2.1, 13.2 Hz, 1H), 7.54-7.31 (m, 5H), 7.14-7.1 (m, 2H),6.9 (brs, 1H), 4.73 (q, J=8.3 Hz. 1H), 3.89 (s, 3H), 1.78-1.63 (m, 2H),1.44-1.32 (m, 4H), 0.83 (t, J=7.1 Hz, 3H); MS (ESI) m/z: 532.2 (M+H⁺).

Example 35

To a solution of thiophenecarboxylic acid (0.5 g, 3.90 mmol) in tBuOH(10 ml) was added Et₃N (0.571 ml, 4.10 mmol) and DPPA (0.883 ml, 4.10mmol). The solution was heated at 90° C. for 4 hours. The reactionmixture was cooled to RT and the solvent was removed in vacuo. Theresidue was treated with benzene and then the solution was washed with5% citric acid, and sat'd NaHCO₃. Solid was filtered off and thefiltrate was washed with brine. The organic layer was dried (MgSO₄),concentrated in vacuo and the residue was purified by silica gel columnchromatography (EtOAc/hexanes) to obtain tert-butylthiophen-2-ylcarbamate (0.39 g, 50% yield). ¹H NMR (400 MHz, DMSO-d₆): δ10.4 (brs, 1H), 6.84 (dd, J=1.6, and 5.2 Hz, 1H), 6.75 (dd, J=4.0, and5.6 Hz, 1H), 6.48 (dd, J=1.6, and 4.0 Hz, 2H), 1.45 (s, 9H); MS (ESI)m/z: 222.0 (M+22+H⁺).

Acetyl chloride (0.36 mL) was added dropwise to a solution of EtOAc (4mL) and MeOH (0.203 mL) at 0° C. A solution of tert-butylthiophen-2-ylcarbamate (0.10 g, 0.502 mmol) in EtOAc (1 mL) was addeddropwise to the reaction mixture while maintaining the temperature under0° C. The solution was stirred for 1 hour (the ice bath was allowed tomelt during this time) and then concentrated to obtain thiophen-2-aminewhich was used for the next reaction without purification.

Example B4 (0.10 g, 0.252 mmol), thiophen-2-amine (0.050 g, 0.505 mmol),and DIEA (0.125 ml, 0.757 mmol) were combined in DMF (2 ml). TBTU (0.105g, 0.328 mmol) was added and the resultant solution was stirredovernight at RT. The reaction was diluted with water and extracted withEtOAc (3×). The combined organic phases were washed with brine, dried(Na₂SO₄), concentrated in vacuo and purified by silica gel columnchromatography (EtOAc/hexanes) to give a residue. The residue wastreated with CH₃CN: H₂O (1:1, 4 mL) and lyophilized to obtainN-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(thiophen-2-yl)cyclopropane-1,1-dicarboxamide(0.025 g, 21% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 11.0 (s, 1H), 10.6(s, 1H), 8.38 (d, J=5.6 Hz, 1H), 8.25 (s, 1H), 7.95 (m, 2H), 7.25 (m,2H), 7.02 (m, 1H), 6.98 (dd, J=1.2, and 5.6 Hz, 1H), 6.83 (m, 2H), 6.68(m, 1H), 3.84 (s, 3H), 1.57 (m, 4H); MS (ESI) m/z: 478.0 (M+H⁺).

Example 36

To a stirring suspension of Example B3 (65 mg, 0.164 mmol), TBTU (79 mg,0.246 mmol) and (R)-1-(4-fluorophenyl)-2-methoxyethanamine (40.5 mg,0.197 mmol; prepared according to the published method: J. Med. Chem.(1999), 42(24), 4981) in DMF (2 ml) was added DIEA (0.171 ml, 0.984mmol). The resulting clear solution was stirred at RT overnight. Afterstirring overnight, the reaction was diluted with satd. NaHCO₃ andextracted with EtOAc (2×). The combined organics were washed with satd.NaHCO₃ (1×), satd. LiCl (2×), and brine (1×), dried (MgSO₄), evaporatedin vacuo and purified by reverse phase chromatography. Pure fractionswere pooled, treated with satd. NaHCO₃ (pH 8) and extracted with EtOAc(3×). The combined organics were washed with satd. NaHCO₃ (1×), brine(1×), dried (MgSO₄), and evaporated to affordN-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′((R)-1-(4-fluorophenyl)-2-methoxyethyl)cyclopropane-1,1-dicarboxamideas an oil. This was dissolved in 4:1 MeCN/H₂O, treated with certified0.1N HCl (1.37 ml, 1.0 eq), frozen and lyophilized to afford 63 mg (66%yield) of the HCl salt as a solid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.64(s, 1H), 8.49-8.48 (m, 2H), 8.44-8.42 (m, 1H), 8.18 (brs, 1H), 7.89-7.85(m, 1H), 7.54 (brs, 1H), 7.48-7.35 (m, 4H), 7.16-7.11 (m, 2H), 6.92(brs, 1H), 5.13-5.06 (m, 1H), 3.89 (s, 3H), 3.61-3.56 (m, 1H), 3.49-3.46(m, 1H), 3.25 (s, 3H), 1.45-1.33 (m, 4H); MS (ESI) m/z: 516.1 (M+H⁺).

Example 37

To a solution of Example B1 (0.070 g, 0.314 mmol) in DMF (1 ml) wasadded Example A8 (0.100 g, 0.314 mmol), Hunigs base (0.078 ml, 0.470mmol) and TBTU (0.151 g, 0.470 mmol). The mixture was stirred overnightat RT and then diluted with EtOAc. The resultant solution was washedwith water and NaHCO₃, dried (Na₂SO₄), concentrated in vacuo andpurified by silica gel column chromatography (EtOAc/hexanes) to give aresidue. The residue was treated with CH₃CN and kept overnight at RT.The solid was filtered and dried under vacuum to obtainN-(4-fluorophenyl)-N′-(4-(2-(4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yloxy)phenyl)cyclopropane-1,1-dicarboxamide(0.105 g, 64% yield). ¹H NMR (400 MHz, DMSO-d₆, major isomer): δ 13.5(s, 1H), 10.2 (s, 1H), 10.1 (s, 1H), 8.52 (d, J=5.6 Hz, 1H), 7.84 (m,1H), 7.75 (m, 2H), 7.62 (m, 2H), 7.35 (d, J=2.8 Hz, 1H), 7.14 (m, 2H),7.12 (m, 3H), 7.06 (dd, J=2.4, and 5.6 Hz, 1H), 1.44 (m, 4H); MS (ESI)m/z: 526.1 (M+H⁺).

Example 38

To a solution of Example B1 (0.100 g, 0.448 mmol) in dichloromethane (5ml) was added Example A22 (0.120 g, 0.448 mmol) followed by Bop-chloride(0.228 g, 0.896 mmol) and diisopropylethylamine (0.116 g, 0.896 mmol).The reaction mixture was stirred at RT for 15 hours, concentrated invacuo, stirred with water, filtered, washed and dried. The solid waspurified by chromatography (ethyl acetate/hexanes) to provideN-(4-fluorophenyl)-N′-(6-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)pyridin-3-yl)cyclopropane-1,1-dicarboxamide(0.055 g, 26% yield) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆ δ□10.25 (s, 1H), 10.03 (s, 1H), 8.45 (s, 1H), 8.40 (m, 1H), 8.25 (s, 1H),8.18 (m, 1H), 8.00 (s, 1H), 7.60 (m, 2H), 7.40 (s, 1H), 7.16 (m 3H),6.85 (m, 1H), 3.80 (s, 3H), 1.40 (s, 4H); MS (ESI) m/z: 473.1 (M+H⁺).

Example 39

To a solution of 4-fluorophenylacetyl chloride (0.500 g, 2.90 mmol) intoluene (8.0 ml) was added silver cyanate (0.456 g, 3.05 mmol) at RT.The reaction mixture was shielded from light and heated to reflux. After2 hours, the mixture was cooled to RT and the solution was filteredusing 0.45 μM Teflon syringe filter. The filtrate,2-(4-fluorophenyl)acetyl isocyanate solution (0.4M: 0.52 g/7 mL) wasused as is in the next reaction.

To a solution of 2-(4-fluorophenyl)acetyl isocyanate (4.68 ml, 1.873mmol) in toluene (4.68 ml) was added Example A8 (0.10 g, 0.312 mmol) toform a heterogeneous mixture. THF (5 mL) was added and the reactionmixture was stirred overnight at RT. The solid was filtered and purifiedby silica gel column chromatography (EtOAc/hexanes) to obtain1-(2-(4-fluorophenyl)acetyl)-3-(4-(2-(4-(trifluoromethyl)-1,1-imidazol-2-yl)pyridin-4-yloxy)phenyl)urea(0.097 g, 62% yield). ¹H NMR (400 MHz, DMSO-d₆, major isomer): δ 13.5(s, 1H), 11.0 (s, 1H), 10.5 (s, 1H), 8.52 (d, J=5.6 Hz, 1H), 7.83 (m,1H), 7.64 (m, 2H), 7.1-7.4 (m, 7H), 7.04 (dd, J=2.8, and 5.6 Hz, 1H),3.71 (s, 2H); MS (ESI) m/z: 500.1 (M+H⁺).

Example 40

To a solution of Example B5 (9.91 g, 23.58 mmol) in DMF (80 mL), underan atmosphere of argon, were added TBTU (11.36 g, 35.4 mmol), DIPEA(20.59 ml, 118 mmol) and 4-fluoroanline (3.93 g, 35.4 mmol). Thereaction mixture was stirred at RT overnight. An additional portion ofTBTU (7.5 g, 17.8 mmol) was added and stirring was continued. After 2 h,an additional portion of TBTU (3.5 g, 8.33 mmol) was added and stirringwas continued for 2 h. The solvent was removed under high vacuum and theresidue was dissolved in EtOAc (700 mL) and washed with sat. aq. NaHCO₃(2×200 mL) and brine (50 mL), dried (MgSO₄), concentrated to dryness andpurified by silica gel chromatography (MeOH-DCM) to provideN-(2,5-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(7.2 g, 59% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 11.14 (s, 1H), 9.76 (s,1H), 8.39 (d, J=5.6 Hz, 1H), 8.28 (s, 1H), 8.13 (dd, J=12.1, 7.1 Hz,1H), 7.99 (s, 1H), 7.62-7.53 (m, 3H), 7.27 (d, J=2.6 Hz, 1H), 7.22-7.15(m, 2H), 6.71 (dd, J=5.6, 2.4 Hz, 1H), 3.86 (s, 3H), 1.69-1.56 (m, 4H);MS (ESI): m/z 508.1 [M+1]⁺.

Example 41

To a solution of Example B1 (0.100 g, 0.448 mmol) in dichloromethane (5ml) was added Example A13 (0.120 g, 0.448 mmol), followed byBop-chloride (0.228 g, 0.896 mmol) and diisopropylethylamine (0.116 g,0.896 mmol). The reaction mixture was stirred at RT for 15 hours,concentrated in vacuo, stirred with water, filtered, washed, dried andcrystallized (acetonitrile) to provideN-(4-fluorophenyl)-N′-(5-(2-(1-methyl-1,4-pyrazol-4-yl)pyridin-4-yloxy)pyridin-2-yl)cyclopropane-1,1-dicarboxamide(0.005 g, 2.3% yield) as a solid. ¹H NMR (400 MHz, DMSO-d₆ δ 9.70 (s,1H), 8.40 (d, J=5 Hz, 1H), 8.26 (s, 1H), 8.15 (d, J=11 Hz, 1H), 7.98 (s,1H), 7.65 (dd, J=9, 5 Hz, 1171), 7.60 (m, 2H), 7.20 (brs, 1H), 7.15 (m,2H), 6.70 (m, 1H), 3.80 (s, 3H), 1.60 (m, 2H), 1.50 (m, 2H); MS (ESI)m/z: 473.2 (M+H⁺).

Example 42

4-Fluorophenylacetic acid (1 g, 6.49 mmol) was dissolved in acetonitrile(40 ml) and cooled to 0° C. in an ice bath.1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.492 g,7.79 mmol) was added, followed by 1-hydroxybenzotriazole (1.19 g, 7.79mmol). The mixture was stirred at 0° C. for 2.5 hours, and thenconcentrated ammonium hydroxide (0.865 ml, 13.0 mmol) was added slowly.The mixture then stirred at RT for an additional 2 hours. After thistime the solids were filtered off, and the filtrate was diluted withethyl acetate (50 mL). The solution was washed with saturated aqueousNaHCO₃ (2×50 mL) and brine (50 mL), dried (MgSO₄) and concentrated invacuo to yield 2-(4-fluorophenyl)acetamide (0.87 g, 88% yield) as awhite solid which was used as is in the next reaction. ¹H NMR (400 MHz,DMSO-d₆): δ 7.45 (broad s, 1H), 7.26 (m, 2H), 7.09 (m, 2H), 6.87 (broads, 1H), 3.34 (s, H).

2-(4-Fluorophenyl)acetamide (0.046 g, 0.298 mmol) was dissolved indichloroethane (3 ml) and oxalyl chloride (0.026 ml, 0.298 mmol) wasadded. The mixture was heated in an 85° C. oil bath under a balloon ofargon for 14 hours. The reaction mixture was then cooled to RT andconcentrated to dryness under reduced pressure. It was dissolved in NMP(1.5 ml) and Example A12 (0.045 g, 0.149 mmol) was added. The mixturestirred for 1.5 hours at RT and was then diluted with ethyl acetate (50mL), washed with water (3×50 mL) and brine (50 mL), dried (MgSO₄),concentrated in vacuo and purified via silica gel chromatography(THF-hexanes) to yield1-(2,5-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)ureaas an off-white solid (0.059 g, 82% yield). ¹H NMR (400 MHz, DMSO-d₆): δ11.26 (s, 1H), 10.89 (s, 1H), 8.36 (d, 1H), 8.26 (s, 1H), 8.18 (dd, 1H),7.97 (s, 1H), 7.59 (dd, 1H), 7.34 (m, 2H), 7.22 (d, 1H), 7.16 (m, 2H),6.70 (dd, 1H), 3.84 (s, 3H), 3.74 (s, 2H); MS (ESI) m/z: 482.1 (M+H⁺).

Example 43

4-Fluorophenylacetyl chloride (0.5 g, 2.90 mmol) was added to asuspension of silver cyanate (1.30 g, 8.70 mmol) in toluene (8 ml) atRT. The reaction mixture was shielded from light and heated to reflux.After 2 h, the mixture was cooled to RT and filtered. The filtratecontaining 2-(4-fluorophenyl)acetyl isocyanate (0.363 M) was usedwithout further purification. An aliquot of the 2-(4-fluorophenyl)acetylisocyanate solution (0.363 M in toluene, 3.5 mL, 1.271 mmol) was treatedwith Example A3 (0.192 g, 0.635 mmol) and the mixture was stirred at RTovernight. The resultant precipitate was collected by filtration andfurther purified by reverse-phase silica gel chromatography(acetonitrile/water (0.1% TFA)). Pure fractions were combined,concentrated, basified with NaHCO₃ and extracted with EtOAc (2×). Thecombined extracts were washed with brine, dried (MgSO₄) and concentratedin vacuo to provide1-(2,3-difluoro-4-(2-(1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea(0.066 g, 22% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ11.25 (s, 1H), 10.84 (s, 1H), 8.39 (d, J=5.6 Hz, 1H), 8.28 (s, 1H),8.01-7.97 (m, 2H), 7.39-7.35 (m, 2H), 7.27 (d, J=2.5 Hz, 1H), 7.26-7.21(m, 1H), 7.21-7.15 (m, 2H), 6.75 (dd, J=5.6, 2.6 Hz, 1H), 3.86 (s, 3H),3.76 (s, 2H); MS (ESI) m/z: 482.1 (M+H+).

Example 44

2-(4-Fluorophenyl)acetamide from Example 42 (0.115 g, 0.748 mmol) wasdissolved in dichloroethane (8 ml) and oxalyl chloride (0.082 ml, 0.935mmol) was added. The mixture was stirred at 85° C. under a balloon ofargon for 18 hours. The mixture was cooled to RT, evaporated to dryness,and added to a solution of Example A13 (0.357 g, 0.935 mmol) in NMP (5ml). The mixture was stirred at RT for 45 minutes, diluted with ethylacetate (50 mL), washed with water (2×50 mL) and brine (50 mL) dried(MgSO₄), concentrated under reduced pressure and purified via silica gelchromatography (THF-hexanes) to yield1-(2-(4-fluorophenyl)acetyl)-3-(5-(2-(1-methyl-1,1-pyrazol-4-yl)pyridin-4-yloxy)pyridin-2-urea(0.185 g, 54% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 11.12 (s, 1H), 10.93(s, 1H), 8.36 (d, 1H), 8.24 (m, 2H), 8.07 (d, 1H), 7.96 (s, 1H), 7.72(dd, 1H), 7.35 (m, 2H), 7.18 (m, 3H), 6.69 (dd, 1H), 3.83 (s, 3H), 3.74(s, 2H); MS (ESI) m/z: 447.2 (M+H⁺).

Example 45

Using a procedure analogous to Example 2, Example B5 (0.11 g, 0.265mmol), diisopropylethylamine (0.051 ml, 0.292 mmol), aniline (1.004 ml,0.345 mmol) and TBTU (0.111 g, 0.345 mmol) were combined and purifiedvia silica gel chromatography (methanol-methylene chloride) to yieldN-(2,5-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-phenylcyclopropane-1,1-dicarboxamideas a clear film (0.030 g, 23% yield). MS (ESI) m/z: 490.2 (M+H⁺).

N-(2,5-Difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-phenylcyclopropane-1,1-dicarboxamidewas dissolved in acetonitrile (5 ml) and 4M HCl in dioxane (0.068 ml,0.274 mmol) was added slowly with stirring. The mixture was stirred for1.5 hours at RT as a white solid slowly precipitated from the solution.The salt was collected via suction filtration and washed with diethylether. A suspension of the product in a 4:1 mix of acetonitrile andwater was lyophilized overnight to obtainN-(2,5-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-phenylcyclopropane-1,1-dicarboxamidehydrochloride as a white powder (0.047 g, 65% yield). ¹H NMR (400 MHz,DMSO-d₆): δ 11.18 (s, 1H), 9.64 (s, 1H), 8.43 (m, 2H), 8.13 (m, 2H),7.60 (m, 1H), 7.51 (m, 3H), 7.28 (m, 2H), 7.05 (m, 1H), 6.97 (broad s,1H), 3.84 (s, 3H), 1.63 (m, 2H), 1.53 (m, 2H); MS (ESI) m/z: 490.2(M+H⁺).

Example 46

4-Fluorophenylacetic acid (0.144 g, 0.941 mmol) was dissolved indichloroethane (9.51 ml) and oxalyl chloride (0.082 ml, 0.941 mmol) wasadded. The mixture was heated in an 85° C. oil bath under argon for 14hours, cooled to RT and concentrated under reduced pressure. The crudeyellow oil was then re-dissolved in NMP (4.75 ml) and Example A14 (0.15g, 0.471 mmol) was added. The mixture was stirred for 2.5 hours at RT,diluted with ethyl acetate (70 mL), washed with water (2×40 mL) andbrine (40 mL), dried (MgSO₄), concentrated in vacuo and purified viasilica gel chromatography (ethyl acetate/hexanes) to yield1-(5-chloro-2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)ureaas a white solid. It was triturated in DCM (4 mL) and ethyl acetate (0.2mL) and collected by suction filtration to give1-(5-chloro-2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea(0.1456 g, 62% yield). MS (ESI) m/z: 498.1 (M+H⁺).

1-(5-Chloro-2-fluoro-4-(2-O-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea(0.146 g, 0.293 mmol) was fully dissolved in a mixture of THF (4 ml),acetonitrile (4 mL), and methanol (0.5 mL). Methanesulfonic acid (19 μl,0.293 mmol) was added, and after stirring for several minutes aprecipitate started to form. The mixture was stirred at RT for 5 hours.1-(5-Chloro-2-fluoro-4-(2-(1-methyl-1,4-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)ureamesylate salt was obtained by suction filtration and was washed withacetonitrile (0.148 g, 82% yield). ¹H NMR (500 MHz, DMSO-d₆): δ 11.33(s, 1H), 10.97 (s, 1H), 8.59 (m, 2H), 8.46 (d, 1H), 8.26 (s, 1H), 7.74(d, 1H), 7.65 (s, 1H), 7.36 (m, 2H), 7.17 (m, 3H), 3.92 (s, 3H), 3.77(s, 2H), 2.33 (s, 31-1); MS (ESI) m/z: 498.1 (M+H⁺).

Example 47

Example B1 (1.484 g, 6.65 mmol) was dissolved in thionyl chloride (14ml, 192 mmol) at 60° C. The reaction mixture stirred for 30 minutesunder argon, then the solution was cooled to RT and the mixture wasazeotroped with toluene (4×10 mL) to give1-((4-fluorophenyl)carbamoyl)cyclopropanecarbonyl chloride as anoff-white solid, which was used in the next step without purification,assuming a 100% yield. MS (ESI) m/z (methanol quench): 238.1 (M+H⁺).

Example A14 (1.696 g, 5.32 mmol) was dissolved in THF (15 ml) and addedto 1-((4-fluorophenyl)carbamoyl)cyclopropanecarbonyl chloride (1.545 g,6.39 mmol), followed by triethylamine (0.964 ml, 6.92 mmol). The mixturewas stirred at RT for 5 minutes and then the mixture was filtered toremove triethylamine HCl. The filtrate was concentrated under reducedpressure and purified via silica gel chromatography (DCM/MeOH) to yieldN-(5-chloro-2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a white foam (2.55 g, 91% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 11.03(s, 1H), 9.77 (s, 1H), 8.37 (d, 1H), 8.27 (m, 2H), 7.97 (s, 1H), 7.57(m, 3H), 7.22 (d, 1H), 7.16 (m, 2H), 6.61 (dd, 1H), 3.84 (s, 3H), 1.64(m, 2H) 1.56 (m, 2H); MS (ESI) m/z: 524.2 (M+H⁺).

Example 48

A suspension of silver cyanate (0.434 g, 2.90 mmol) in toluene (8.0 ml)was treated with 4-fluorophenylacetyl chloride (0.397 ml, 2.90 mmol),the mixture shielded from light and heated to reflux for 2 hours. Themixture was cooled to RT, filtered through a syringe filter, treatedwith Example A10 (0.438 g, 1.449 mmol) and stirred overnight at RT. Thesolid was filtered, rinsed with a small amount of toluene and dried in avacuum oven at 70° C. for 2 days to afford1-(3,5-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea(620 mg, 89% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): 3.74(s, 2H), 3.84 (s, 3H), 6.71 (dd, 1H), 7.15 (t, 2H), 7.27 (d, 1H), 7.34(m, 2H), 7.62 (d, 2H), 7.98 (s, 1H), 8.27 (s, 1H), 8.37 (d, 1H), 10.65(s, 1H), 11.10 (s, 1H); MS (ESI) m/z: 482.2 (M+H⁺).

Example 49

Example B1 (0.241 g, 1.078 mmol) was dissolved in thionyl chloride (4ml, 54.8 mmol) and heated at 60° C. for 3 h. The reaction was azeotropedwith toluene (3×). The crude acid chloride was dissolved in THF (5 ml)and added dropwise to a 0° C. solution of Example A15 (0.31 g, 0.980mmol) and N,N-diisopropylethylamine (0.171 ml, 0.980 mmol) in THF (5ml). The mixture was stirred overnight at RT, saturated aq. NaHCO₃ (25ml) was added and the mixture extracted with EtOAc (3×25 ml). Thecombined organic extracts were dried (Na₂SO₄), evaporated and purifiedby silica gel chromatography (hexanes/EtOAc) to elute two products.N-(4-(2-(1,3-Dimethyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(278 mg; 54.4%) (eluted first) andN-(4-(2-(1,5-dimethyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(81 mg; 16%) (eluted second).N-(4-(2-(1,3-Dimethyl-1,4-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide:¹H NMR (400 MHz, DMSO-d₆): δ 11.07 (s, 1H), 9.75 (s, 1H), 8.42 (d, 1H),8.12-8.07 (m, 1H), 7.85 (s, 1H), 7.83-7.15 (m, 4H), 7.20-7.12 (m, 2H),6.68-6.6.66 (m, 1H), 3.75 (s, 3H), 2.54 (s, 3H), 1.67-1.64 (m, 2H),1.58-1.55 (m, 2H); MS (ESI) m/z: 522.2 (M+H⁺).N-(4-(2-(1,5-Dimethyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide:¹H NMR (400 MHz, DMSO-d₆): δ 11.10 (s, 1H), 9.74 (s, 1H), 8.41 (d, 1H),8.14-8.08 (m, 2H), 7.59-7.53 (m, 4H), 7.19-7.14 (m, 1H), 7.07 (d, 1H),6.72-6.70 (m, 3.75 (s, 3H), 2.36 (s, 3H), 1.67-1.64 (m, 2H), 1.58-1.55(m, 2H); MS (ESI) m/z: 522.2 (M+H⁺).

N-(4-(2-(1,3-Dimethyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(0.278 g, 0.533 mmol) was dissolved in THF (5 ml) and warmed untilreflux. Methanesulfonic acid (0.035 ml, 0.533 mmol) was added. Aprecipitate immediately formed. The mixture was sonicated for 10 min andallowed to cool to RT. The precipitate was filtered off and driedovernight in the drying pistol (80° C.) to yieldN-(4-(2-(1,3-Dimethyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamidemesylate (234 mg, 71.1% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 11.20 (s,1H), 9.71 (s, 1H), 8.57 (d, 1H), 8.19-8.14 (m, 1H), 7.90 (s, 1H),7.66-7.62 (m, 1H), 7.58-7.55 (m, 2H), 7.38 (s, 1H), 7.19-7.14 (m, 2H),7.05-7.02 (m, 1H), 3.79 (s, 3H), 2.34 (s, 3H), 2.29 (s, 3H), 1.68-1.65(m, 2H), 1.58-1.56 (m, 2H); MS (ESI) m/z: 522.2 (M+H⁺).

Example 50

N-(4-(2-(1,5-Dimethyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamidefrom Example 49 (0.081 g, 0.155 mmol) was dissolved in THF (2.5 ml) andwarmed until reflux. Methanesulfonic acid (10.09 μl, 0.155 mmol) wasadded and the mixture cooled to RT. The mixture was slowly diluted withEt₂O (5 ml). A precipitate immediately began to form upon addition.After the addition was complete, the mixture was sonicated for 20 min.The precipitate was filtered off to yieldN-(4-(2-(1,5-dimethyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamidemesylate (79 mg, 82% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 11.18 (s, 1H),9.72 (s, 1H), 8.52 (d, 1H), 8.20-8.14 (m, 2H), 7.63-7.56 (m, 3H), 7.25(s, 1H), 7.18-7.14 (m, 2H), 6.99-6.94 (m, 1H), 3.74 (s, 3H), 2.35 (s,3H), 2.28 (s, 3H), 1.67-1.64 (m, 2H), 1.58-1.55 (m, 214); MS (ESI) m/z:522.2 (M+H⁺).

Example 51

1-((4-fluorophenyl)carbamoyl)cyclopropanecarbonyl chloride prepared viathe procedure in Example 47 (0.13 g, 0.538 mmol), Example A9 (0.123 g,0.414 mmol), and triethylamine (0.065 ml, 0.621 mmol) were dissolved inTHF (3 ml). The mixture was stirred at RT for 30 min, filtered to removetriethylamine HCl, concentrated under reduced pressure and purified bysilica gel column chromatography (MeOH/DCM) to obtainN-(2-fluoro-5-methyl-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(0.067 g, 32% yield). MS (ESI) m/z: 504.2 (M+H⁺).

N-(2-fluoro-5-methyl-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(0.067 g, 0.133 mmol) was dissolved in CH₂Cl₂ (1 ml), 1.0 Mmethanesulfonic acid (0.133 ml, 0.133 mmol) was added and the reactionmixture was stirred at RT for 1 hour. The solid was filtered to obtainN-(2-fluoro-5-methyl-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamidemethanesulfonate salt (55 mg, 67% yield). ¹H NMR (400 MHz, DMSO-d₆): δ10.8 (brs, 1H), 9.81 (s, 1H), 8.53 (m, 2H), 8.18 (m, 1H), 8.01 (m, 1H),7.57 (m, 3H), 7.32 (m, 1H), 7.16 (m, 2H), 6.94 (m, 1H), 3.90 (s, 3H),2.29 (s, 3H), 2.09 (s, 3H), 1.5-1.7 (m, 4H).

Example 52

A solution of Example All (0.107 g, 0.359 mmol) and triethylamine (0.075ml, 0.538 mmol) in THF (3.0 ml) was sparged with argon for severalminutes, treated with 1-((4-fluorophenyl)carbamoyl)cyclopropanecarbonylchloride from Example 51 (0.130 g, 0.538 mmol) and the mixture stirredat RT under an argon atmosphere for 30 minutes. The mixture wasfiltered, rinsed with THF and the filtrate concentrated to dryness. Theresulting residue was triturated with diethyl ether, sonicated forseveral minutes and the resulting solid filtered, rinsed with Et₂O anddried in vacuo to affordN-(2-fluoro-4-methyl-5-(4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(154 mg, 85% yield) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆):1.52 (m, 2H), 1.57 (m, 2H), 2.04 (s, 3H), 3.87 (s, 3H), 7.15 (t, 2H),7.25 (d, 1H), 7.44 (d, 1H), 7.56 (m, 214), 7.71 (d, 1H), 8.08 (s, 1H),8.43 (m, 211), 9.83 (brs, 1H), 10.71 (brs, 1H); MS (ESI) m/z: 505.2(M+H⁺).

Example 53

To a suspension of Example B1 (0.293 g, 1.315 mmol) and cyanuricchloride (0.097 g, 0.526 mmol) in acetonitrile (5 ml) was addedN-methylpyrrolidine (0.112 g, 1.32 mmol) and the reaction was stirred atRT for 20 minutes. To this reaction mixture was added Example A16 (0.250g, 0.876 mmol), and stirring continued at RT for 13 hours. The reactionmixture was concentrated in vacuo, the residue stirred indichloromethane, filtered, washed and dried. The resultant solid wasstirred in hot methanol, cooled to RT, filtered, washed and dried toprovideN-(2-fluoro-5-(4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(0.096 g, 22% yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.15(s, 1H), 10.89 (s, 1H)), 9.79 (s, 1H), 8.47 (d, J=5 Hz, 1H), 8.42 (s,1H), 8.08 (s, 1H), 7.86 (s, 1H), 7.57 (m, 1H), 7.45 (d, J=5.7 Hz, 1H),7.32 (dd, J=9, 11.5 Hz, 1H), 7.15 (t, J=9 Hz, 2H), 7.00 (m, 1H), 3.87(s, 3H), 1.60 (m, 2H), 1.53 (m, 2H); MS (ESI) m/z: 491.2 (M+H⁺).

Example 54

1-((4-Fluorophenyl)carbamoyl)cyclopropanecarbonyl chloride from Example51 (0.13 g, 0.538 mmol), Example A20 (0.102 g, 0.359 mmol), andtriethylamine (0.075 ml, 0.717 mmol) were dissolved in THF (3 ml). Themixture was stirred at RT. After 1 hour, the reaction was filtered toremove triethylamine HCl, concentrated in vacuo, and purified by silicagel column chromatography (EtOAc/hexanes) to obtain a residue. Theresidue was treated with Et₂O. The solid formed was filtered and driedto obtainN-(5-(4-(1H-pyrazol-4-yl)pyrimidin-2-yloxy)-2-fluoro-4-methylphenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(80 mg, 45% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 13.3 (s, 1H), 10.7 (s,1H), 9.84 (s, 1H), 8.49 (s, 1H), 8.43 (d, J=5.2 Hz, 1H), 8.11 (d, J=1.6Hz, 1H), 7.70 (d, J=7.2 Hz, 1H), 7.56 (m, 2H), 7.49 (d, J=5.2 Hz, 1H),7.25 (d, J=11.6 Hz, 1H), 7.13 (m, 2H), 2.05 (s, 3H), 1.58 (m, 2H), 1.51(m, 2H); MS (ESI) m/z: 491.2 (M+H⁺).

Example 55

A solution of Example B1 (196 mg, 0.811 mmol) in THF (2 mL) was added toa stirred mixture of triethylamine (200 mg, 2.212 mmol) and Example A18(200 mg, 0.737 mmol) in THF (4 mL). The mixture was then stirred at RT.The mixture was further treated with Example B1 (˜75 mg) in THF (1 mL).The mixture was stirred at RT for 3 hrs, then diluted with ethyl acetate(30 mL) and washed with 10% potassium carbonate (30 mL), brine (30 mL),dried (Na₂SO₄), evaporated at reduced pressure and purified by reversephase chromatography (CH₃CN/H₂O with 0.1% TFA) to give an aqueousresidue was then treated with saturated sodium bicarbonate (4 mL) andallowed to precipitate. The solid was collected by filtration, washedwith water (1 mL) and dried on a high vacuum line at 80° C. to giveN-(5-(4-(1H-pyrazol-4-yl)pyrimidin-2-yloxy)-2-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(26 mg, 7% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 1.50-1.60 (pa, 4H),6.90-7.01 (m, 1H), 7.15 (t, 2H), 7.31 (t, 1H), 7.49-7.50 (m, 1H),7.55-7.58 (m, 2H), 7.84-7.85 (m, 1H), 8.15 (br. s, 1H), 8.46 (d, 1H),8.50 (br. s, 1H), 9.80 (s, 1H), 10.87 (s, 1H), 13.3 (s, 1H); MS (ES-API)m/z: 477.2 (M+H⁺).

Example 56

2-(4-Fluorophenyl)acetamide from Example 42 (0.091 g, 0.597 mmol) wasdissolved in dichloroethane (6 ml) and oxalyl chloride (0.052 ml, 0.597mmol) was added. The mixture was heated at 85° C. under a balloon ofargon for 15 hours. The reaction mixture was cooled to RT and thesolvent was removed under reduced pressure. The residue that remainedwas dissolved in NMP (3.00 ml) and added to Example A17 (0.084 g, 0.299mmol). The solution stirred at RT for 30 minutes under argon. Thereaction mixture was diluted with a 4:1 mixture of ethyl acetate and THF(60 mL) and washed with 10% aqueous LiCl (2×50 mL) and brine (50 mL),dried (MgSO₄), evaporated in vacuo and purified via silica gelchromatography (ethyl acetate/hexanes) to yield1-(2-(4-fluorophenyl)acetyl)-3-(4-methyl-5-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)pyridin-2-yl)ureaas an off-white solid (0.097 g, 71% yield). ¹H NMR (400 MHz, DMSO-d₆): δ11.11 (s, 1H), 10.89 (s, 1H), 8.33 (d, 1H), 8.24 (s, 1H), 8.12 (s, 1H),8.00 (s, 1H), 7.95 (s, 1H), 7.35 (m, 2H), 7.25 (m, 1H), 7.14 (m, 2H),6.59 (dd, 1H), 3.83 (s, 3H), 3.74 (s, 2H), 2.15 (s, 3H); MS (ESI) m/z:461.1 (M+H⁺).

Example 57

Example B1 (0.092 g, 0.412 mmol) was dissolved in thionyl chloride (6ml, 82 mmol) and heated at 80° C. for 1 h. The mixture was cooled andazeotroped with toluene (3×10 ml). The crude acid chloride was dissolvedin THF (5 ml) and added dropwise to a 0° C. solution of Example A19(0.113 g, 0.375 mmol) and N,N-diethylisopropylamine (0.131 ml, 0.749mmol) in THF (5 ml). The mixture was stirred overnight at RT. Thereaction was not complete. Additional acid chloride was generated fromExample B1 (65 mg, 0.29 mmol) using the above method. The crude acidchloride was dissolved in THF (5 ml) and added to the reaction mixture.The solution was stirred at RT for 4 h, diluted with EtOAc and washedwith sat. NaHCO₃ _((aq)) . The organic extract was dried, evaporated andpurified by silica gel chromatography (hexanes/EtOAc) and reverse phasechromatography (water (0.1% TFA)/acetonitrile (0.1% TFA)), treated withsat. NaHCO₃ _((aq)) until basic and the resulting solid removed byfiltration. The solid was dried under vacuum at 80° C. to yieldN-(2,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-Y-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(57 mg, 30% yield). The mesylate salt was formed by takingN-(2,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(0.057 g, 0.112 mmol) and dissolving it in refluxing acetonitrile (5ml). Methanesulfonic acid (7.29 μl, 0.112 mmol) was added and themixture was cooled to RT, concentrated 2 ml) and ether (5 ml) was addeddropwise. A solid precipitated. The resulting mixture was sonicated for30 min. The solid was filtered off and dried overnight in the dryingpistol to yieldN-(2,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamidemesylate (50 mg, 74% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 11.27 (s, 1H),9.74 (s, 1H), 9.11 (s, 1H), 8.49 (d, 1H), 8.43 (s, 1H), 8.22-8.19 (m,1H), 8.16 (d, 1H), 7.74-7.70 (m, 1H), 7.60-7.57 (m, 2H), 7.21-7.15 (m,3H), 3.92 (s, 3H), 2.34 (s, 3H), 1.71-1.68 (m, 2H), 1.61-1.59 (m, 2H);MS (ESI) m/z: 508.2 (M+H⁺).

Example 58

Using a procedure analogous to Example B1, 1,1-cyclopropanedicarboxylicacid (2 g, 15.37 mmol), Et₃N (2.14 mL, 15.4 mmol), thionyl chloride(1.12 mL, 15.4 mmol), and 4-fluoro-N-methylaniline (1.83 g, 14.6 mmol)were combined to provide1-((4-fluorophenyl)(methyl)carbamoyl)cyclopropanecarboxylic acid (2.79g, 72% yield). MS (ESI) m/z: 260.0 (M+Na⁺).

Example A2 (136 mg, 0.479 mmol),1-((4-fluorophenyl)(methyl)carbamoyl)cyclopropanecarboxylic acid (125mg, 0.525 mmol), TBTU (0.169 g, 0.525 mmol) and i-Pr₂NEt (0.18 mL, 1.050mmol) were combined in DMF (3 mL). The resultant mixture was stirredovernight at RT. Additional portions of TBTU (0.169 g, 0.525 mmol) andi-Pr₂NEt (0.18 mL, 1.05 mmol) were added and the mixture was stirred anadditional 24 h. The reaction mixture was poured into water (30 mL) andextracted with EtOAc (3×30 mL). The organic extracts were washed withsatd aq NaHCO₃ and brine, were dried (MgSO₄), and were concentrated invacuo. The residue was dissolved in CH₂Cl₂ (20 mL) and the solution wasshaken overnight with polymer-bound isocyanate resin (1.7 mmol/g; 0.5g). The mixture was filtered and the filtrate was concentrated todryness and purified by reverse phase chromatography (acetonitrile (with0.1% TFA added)/water (with 0.1% TFA added)). The pure fractions werecombined and concentrated to dryness. THF (10 mL) and polymer-boundcarbonate resin (200 mg) were added to the residue and the mixture wasshaken for 2 h. The mixture was filtered and the filtrate was treatedwith aq HCl (2 N, 2 mL, 4 mmol). The solution was concentrated in vacuo,dissolved in acetonitrile-water (1:1, 6 mL), frozen and lyophilized toprovideN-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)-N-methylcyclopropane-1,1-dicarboxamideHCl salt as a yellow powder (50 mg, 18% yield). ¹H NMR (400 MHz,DMSO-d₆): δ 10.00 (br s, 1H), 8.70 (s, 1H), 8.54 (d, 1H), 8.38 (s, 1H),7.73 (s, 1H), 7.51 (br s, 1H), 7.44-7.20 (m, 4H), 7.15-6.97 (m, 3H),3.93 (s, 3H), 3.23 (s, 3H), 1.43 (s, 2H), 1.22 (s, 2H); MS (ESI) ism/z:504.1 (M+H⁺).

Example 59

Thionyl chloride (1 ml, 13.70 mmol) was added to Example B1 (0.131 g,0.589 mmol; DP-4180) and mixture was stirred at 60° C. under Aratmosphere for 30 min. The mixture was concentrated in vacuo andazeotroped with toluene (2×8 mL) to furnish acid chloride as a whitesolid. To this solid added a solution of Example A21 (0.12 g, 0.421mmol) and triethylamine (0.292 ml, 2.10 mmol) in THF (3 mL) and thereaction was stirred for 1 h at RT. The mixture was partitioned betweenEtOAc (30 mL) and NaHCO₃ solution (30 mL). The aqueous layer wasextracted with EtOAc (1×20 mL) and combined organics were washed withbrine, dried (Na₂SO₄), concentrated in vacuo and purified bychromatography (ethylacetate/hexanes) to affordN-(2-fluoro-4-(2-(3-methylisoxazol-5-yl)pyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(87 mg, 42% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.06(s, 1H), 9.92 (s, 1H), 8.57 (d, J=5.6 Hz, 1H), 7.97 (t, J=8.8 Hz, 1H),7.61-7.57 (m, 2H), 7.37 (d, J=2.4 Hz 1H), 7.34 (dd, J=11.6 Hz, 2.4 Hz,1H), 7.15 (t, J=9.2 Hz, 2H), 7.09 (dd, J=8.8 Hz, 1.6 Hz, 1H), 7.03 (dd,J=5.6 Hz, 2.4 Hz, 1H), 6.96 (s, 1H), 2.28 (s, 3H), 1.58-1.54 (m, 4H); MS(ESI) m/z: 491.2 (M+H⁺).

Example 60

Using a procedure analogous to Example 59, Example B1 (0.113 g, 0.506mmol) was converted to 1-(4-fluorophenylcarbamoyl)cyclopropanecarbonylchloride. To the solid acid chloride was added a solution of Example A23(0.13 g, 0.337 mmol) and triethylamine (0.187 ml, 1.349 mmol) in THF (4mL). The mixture was stirred for 5 h at RT, concentrated in vacuo,dissolved in methanol (4 mL) and 2N aq. NaOH (0.093 mL, 0.186 mmol) wasadded. The mixture was stirred for 30 min at RT, concentrated in vacuo,diluted with 5% citric acid (25 mL) and extracted with EtOAc (2×35 mL).The combined organics were washed with brine, dried (Na₂SO₄),concentrated in vacuo and purified by reverse phase chromatography(acetonitrile/water (0.1% TFA)) to affordN-(4-(2-(1H-1,2,3-triazol-4-yl)pyridin-4-yloxy)-2-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(37 mg, 42% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.49(s, 1H), 9.91 (s, 1H), 8.45 (brs, 1H), 8.17 (s, 1H), 7.90 (t, J=8.8 Hz,1H), 7.55 (dd, J=8.8 Hz, 5.2 Hz, 2H) 7.31 (brs, 1H), 7.29-7.26 (m, 1H),7.10 (t, J=8.8 Hz, 2H), 7.03 (d, J=8.0 Hz, 1H), 6.91 (s, 1H), 1.55-1.50(m, 4H); MS (ESI) m/z: 477.2 (M+H⁺).

Section 4 Biological Data

c-KIT kinase Assay

Activity of c-KIT kinase (Seq. ID no. 1) was determined by following theproduction of ADP from the kinase reaction through coupling with thepyruvate kinase/lactate dehydrogenase system (e.g., Schindler et al.Science (2000) 289: 1938-1942). In this assay, the oxidation of NADH(thus the decrease at A340 nm) was continuously monitoredspectrophometrically. The reaction mixture (100 μl) contained c-KIT(cKIT residues T544-V976, from ProQinase, 5.4 nM), polyE4Y (1 mg/ml),MgCl₂ (10 mM), pyruvate kinase (4 units), lactate dehydrogenase (0.7units), phosphoenol pyruvate (1 mM), and NADH (0.28 mM) in 90 mM Trisbuffer containing 0.2% octyl-glucoside and 1% DMSO, pH 7.5. Testcompounds were incubated with c-KIT (Seq. ID no. 1) and other reactionreagents at 22° C. for <2 min before ATP (200 μM) was added to start thereaction. The absorption at 340 nm was monitored continuously for 0.5hours at 30° C. on Polarstar Optima plate reader (BMG). The reactionrate was calculated using the 0 to 0.5 h time frame. Percent inhibitionwas obtained by comparison of reaction rate with that of a control (i.e.with no test compound). IC₅₀ values were calculated from a series ofpercent inhibition values determined at a range of inhibitorconcentrations using software routines as implemented in the GraphPadPrism software package.

c-KIT with N-terminal GST fusion (Seq ID No. 1)LGYWKIKGLVQPTRLLLEYLEEKYEEHLYERDEGDKWRNKKFELGLEFPNLPYYIDGDVKLTQSMAIIRYIADKHNMLGGCPKERAEISMLEGAVDIRYGVSRIAYSKDFETLKVDFLSKLPEMLKMFEDRLCHKTYLNGDHVTHPDFMLYDALDVVLYMDPMCLDAFPKLVCFKKRIEAIPQIDKYLKSSKYIWPLQGWQATFGGGDHPPKSDLVPRHNQTSLYKKAGSAAAVLEENLYFQGTYKYLQKPMYEVQWKVVEEINGNNYVYIDPTQLPYDHKWEFPRNRLSFGKTLGAGAFGKVVEATAYGLIKSDAAMTVAVKMLKPSAHLTEREALMSELKVLSYLGNHMNIVNLLGACTIGGPTLVITEYCCYGDLLNFLRRKRDSFICSKQEDHAEAALYKNLLHSKESSCSDSTNEYMDMKPGVSYVVPTKADKRRSVRIGSYIERDVTPAIMEDDELALDLEDLLSFSYQVAKGMAFLASKNCIHRDLAARNILLTHGRITKICDFGLARDIKNDSNYVVKGNARLPVKWMAPESIFNCVYTFESDVWSYGIFLWELFSLGSSPYPGMPVDSKFYKMIKEGFRMLSPEHAPAEMYDIMKTCWDADPLKRPTFKQIVQLIEKQISESTNHIYSNLANCSPNRQKPVVDHSVRIN SVGSTASSSQPLLVHDDVc-MET Kinase Assay

Activity of c-MET kinase (Seq. ID no. 2) was determined by following theproduction of ADP from the kinase reaction through coupling with thepyruvate kinase/lactate dehydrogenase system (e.g., Schindler et al.Science (2000) 289: 1938-1942). In this assay, the oxidation of NADH(thus the decrease at A340 nm) was continuously monitoredspectrophometrically. The reaction mixture (100 μl) contained c-MET(c-MET residues: 956-1390, from Invitrogen, catalogue #PV3143, 6 nM),polyE4Y (1 mg/ml), MgCl₂ (10 mM), pyruvate kinase (4 units), lactatedehydrogenase (0.7 units), phosphoenol pyruvate (1 mM), and NADH (0.28mM) in 90 mM Tris buffer containing 0.25 mM DTT, 0.2% octyl-glucosideand 1% DMSO, pH 7.5. Test compounds were incubated with C-Met (Seq. IDno. 2) and other reaction reagents at 22° C. for 0.5 h before ATP (100μM) was added to start the reaction. The absorption at 340 nm wasmonitored continuously for 2 hours at 30° C. on Polarstar Optima platereader (BMG). The reaction rate was calculated using the 1.0 to 2.0 htime frame. Percent inhibition was obtained by comparison of reactionrate with that of a control (i.e. with no test compound). IC₅₀ valueswere calculated from a series of percent inhibition values determined ata range of inhibitor concentrations using software routines asimplemented in the GraphPad Prism software package.

cMET Kinase (Seq ID No. 2)MSYYHHHHHHDYDIPTTENLYFQGAMLVPRGSPWIPFTMKKRKQIKDLGSELVRYDARVHTPHLDRLVSARSVSPTTEMVSNESVDYRATFPEDQFPNSSQNGSCRQVQYPLTDMSPILTSGDSDISSPLLQNTVHIDLSALNPELVQAVQHVVIGPSSLIVHFNEVIGRGHFGCVYHGTLLDNDGKKIHCAVKSLNRITDIGEVSQFLTEGIIMKDFSHPNVLSLLGICLRSEGSPLVVLPYMKHGDLRNFIRNETHNPTVKDLIGFGLQVAKGMKYLASKKFVHRDLAARNCMLDEKFTVKVADFGLARDMYDKEYYSVHNKTGAKLPVKWMALESLQTQKFTTKSDVWSFGVLLWELMTRGAPPYPDVNTFDITVYLLQGRRLLQPEYCPDPLYEVMLKCWHPKAEMRPSFSELVSRISAIFSTFIGEHYVHVNATYVNVKCVAPYPSLLSSEDNADDEVDTRPASF WETS

KDR Kinase Assay Assay K1

The activity of KDR kinase was determined by following the production ofADP from the kinase reaction through coupling with the pyruvatekinase/lactate dehydrogenase system (e.g., Schindler et al. Science(2000) 289: 1938-1942). In this assay, the oxidation of NADH (thus thedecrease at A_(340nm)) was continuously monitoredspectrophotometrically. The reaction mixture (100 μl) contained KDR (SeqID No. 3, 1.5 DM to 7.1 nM, nominal concentration), polyE₄Y (1 mg/ml),pyruvate kinase (3.5 units), lactate dehydrogenase (5.5 units),phosphoenolpyruvate (1 mM), and NADH (0.28 mM) in 60 mM Tris buffercontaining 0.13% octyl-glucoside, 13 mM MgCl₂, 6.8 mM DTT, and 3.5% DMSOat pH 7.5. The reaction was initiated by adding ATP (0.2 mM, finalconcentration). The absorption at 340 nm was continuously monitored for3 h at 30° C. on a Polarstar Optima plate reader (BMG) or instrument ofsimilar capacity. The reaction rate was calculated using the 1 h to 2 htime frame. Percent inhibition was obtained by comparison of reactionrate with that of a control (i.e. with no test compound). IC₅₀ valueswere calculated from a series of percent inhibition values determined ata range of inhibitor concentrations using software routines asimplemented in the GraphPad Prism software package.

Assay K2

KDR kinase assay K2 is the same as for assay K1 except that (1) anominal concentration of 2.1 nM of enzyme was employed (2) the reactionwas pre-incubated at 30° C. for 2 h prior to initiation with ATP and (3)1.0 mM ATP (final concentration) was used to initiate the reaction.

Assay K3

KDR kinase assay K3 is the same as for assay K1 except that (1) anominal concentration of 1.1 nM of enzyme was employed, (2) the buffercomponents per 100 μl reaction mixture were as follows: 75 mM Trisbuffer containing 0.066% octyl-glucoside, 17 mM MgCl₂, and 1% DMSO at pH7.5, (3) the final concentration of DTT was 0.66 mM, (4) the reactionwas pre-incubated at 30° C. for 1 h prior to initiation with ATP, and(5) 1.0 mM ATP (final concentration) was used to initiate the reaction.

KDR protein sequence used for screening (Seq. ID No. 3)DPDELPLDEHCERLPYDASKWEFPRDRLKLGKPLGRGAFGQVIEADAFGIDKTATCRTVAVKMLKEGATHSEHRALMSELKILIHIGHHLNVVNLLGACTKPGGPLMVIVEFCKFGNLSTYLRSKRNEFVPYKVAPEDLYKDFLTLEHLICYSFQVAKGMEFLASRKCIHRDLAARNILLSEKNVVKICDFGLARDIYKDPDYVRKGDARLPLKWMAPETIFDRVYTIQSDVWSFGVLLWEIFSLGASPYPGVKIDEEFCRRLKEGTRMRAPDYTTPEMYQTMLDCWHGEPSQRPTFSELVEHLGNLLQANAQQD

HUVEC Cell Culture

HUVEC (Human umbilical vein endothelial cell) cells were obtained fromLonza (Lonza, Walkersville, Md.). Briefly, cells were grown in EGM-2(Lonza, Walkersville, Md.) at 37 degrees Celsius, 5% CO₂, 95% humidity.Cells were allowed to expand until reaching 90-95% saturation at whichpoint they were subcultured or harvested for assay use. For assay use,cells were harvested and grown in EGM-2 medium supplemented with 2% FBS(Lonza, Walkersville, Md.).

HUVEC VEGF/KDR ELISA

Twenty-five thousand cells were added per well in a 96-well black clearbottom plate (Corning, Corning, N.Y.). Cells were then incubatedovernight at 37 degrees Celsius, 5% CO₂, 95% humidity. A serial dilutionof test compound was dispensed into another 96-well black clear bottomplate (Corning, Corning, N.Y.) containing EBM-2 supplemented with 2%FBS. Compound was added to plates containing cells and incubated for 4hours at 37 degrees Celsius, 5% CO₂, 95% humidity. Cells were stimulatedwith 100 ng/mL VEGF (R&D Systems, Minneapolis, Minn.) for 5 minutes,then lysed. Cell lysates were used to detect phospho-VEGF R2 usingDuoSet IC HUVEC VEGF/KDR ELISA (R&D Systems, Minneapolis, Minn.). Datawas analyzed using Prism software (Graphpad, San Diego, Calif.) tocalculate IC₅₀'s.

EBC-1 Cell Culture

EBC-1 cells (catalog #JCRB0820) were obtained from the Japan HealthScience Research Resources Bank, Osaka, Japan. Briefly, cells were grownin DMEM supplemented with 10% characterized fetal bovine serum(Invitrogen, Carlsbad, Calif.) at 37 degrees Celsius, 5% CO₂, 95%humidity. Cells were allowed to expand until reaching 70-95% confluencyat which point they were subcultured or harvested for assay use.

EBC-1 Cell Proliferation Assay

A serial dilution of test compound was dispensed into a 96-well blackclear bottom plate (Corning, Corning, N.Y.). For each cell line, fivethousand cells were added per well in 200 μL complete growth medium.Plates were incubated for 67 hours at 37 degrees Celsius, 5% CO₂, 95%humidity. At the end of the incubation period 40 μL of a 440 μM solutionof resazurin (Sigma, St. Louis, Mo.) in PBS was added to each well andincubated for an additional 5 hours at 37 degrees Celsius, 5% CO₂, 95%humidity. Plates were read on a Synergy2 reader (Biotek, Winooski, Vt.)using an excitation of 540 nM and an emission of 600 nM. Data wasanalyzed using Prism software (Graphpad, San Diego, Calif.) to calculateIC₅₀ values.

M-NFS-60 Cell Culture

M-NFS-60 cells (catalog #CRL-1838) were obtained from the American TypeCulture Collection (ATCC, Manassas, Va.). Briefly, cells were grown insuspension in RPMI 1640 medium supplemented with 10% characterized fetalbovine serum (Invitrogen, Carlsbad, Calif.), 0.05 mM 2-mercaptoethanol,and 20 ng/mL mouse recombinant macrophage colony stimulating factor(M-CSF) at 37 degrees Celsius, 5% CO₂, and 95% humidity. Cells wereallowed to expand until reaching saturation at which point they weresubcultured or harvested for assay use.

M-NFS-60 Cell Proliferation Assay

A serial dilution of test compound was dispensed into a 384-well blackclear bottom plate (Corning, Corning, N.Y.). Two thousand five hundredcells were added per well in 50 μL complete growth medium. Plates wereincubated for 67 hours at 37 degrees Celsius, 5% CO₂, and 95% humidity.At the end of the incubation period 10 μL of a 440 μM solution ofresazurin (Sigma, St. Louis, Mo.) in PBS was added to each well andincubated for an additional 5 hours at 37 degrees Celsius, 5% CO₂, and95% humidity. Plates were read on a Synergy2 reader (Biotek, Winooski,Vt.) using an excitation of 540 nM and an emission of 600 nM. Data wasanalyzed using Prism software (Graphpad, San Diego, Calif.) to calculateIC₅₀ values.

FMS Kinase Assay

Activity of FMS kinase was determined by following the production of ADPfrom the kinase reaction through coupling with the pyruvatekinase/lactate dehydrogenase system (e.g., Schindler et al. Science(2000) 289: 1938-1942). In this assay, the oxidation of NADH (thus thedecrease at A340 nm) was continuously monitored spectrophometrically.The reaction mixture (100 μl) contained FMS (purchased from Invitrogenor Millipore, 6 nM), polyE4Y (1 mg/ml), MgCl₂ (10 mM), pyruvate kinase(4 units), lactate dehydrogenase (0.7 units), phosphoenol pyruvate (1mM) and NADH (0.28 mM) and ATP (500 μM) in a 90 mM Tris buffercontaining 0.2% octyl-glucoside and 1% DMSO, pH 7.5. The inhibitionreaction was started by mixing serial diluted test compound with theabove reaction mixture. The absorption at 340 nm was monitoredcontinuously for 4 hours at 30° C. on a Polarstar Optima or Synergy 2plate reader. The reaction rate was calculated using the 2 to 3 h timeframe. Percent inhibition was obtained by comparison of reaction ratewith that of a control (i.e. with no test compound). IC₅₀ values werecalculated from a series of percent inhibition values determined at arange of inhibitor concentrations using software routines as implementedin the GraphPad Prism software package.

PDGFRα Kinase Assay

Activity of PDGFRα kinase was determined by following the production ofADP from the kinase reaction through coupling with the pyruvatekinase/lactate dehydrogenase system. In this assay, the oxidation ofNADH (thus the decrease at A340 nm) was continuously monitoredspectrophometrically. The reaction mixture (100 μl) contained PDGFRα(Invitrogen, 10 nM), polyE4Y (1 mg/ml), MgCl₂ (10 mM), pyruvate kinase(4 units), lactate dehydrogenase (0.7 units), phosphoenol pyruvate (1mM) and NADH (0.28 mM) and ATP (500 μM) in a 90 mM Tris buffercontaining 0.2% octyl-glucoside and 1% DMSO, pH 7.5. The inhibitionreaction was started by mixing serial diluted test compound with theabove reaction mixture. The absorption at 340 nm was monitoredcontinuously for 4 hours at 30° C. on a Polarstar Optima or Synergy 2plate reader. The reaction rate was calculated using the 2 to 3 h timeframe. Percent inhibition was obtained by comparison of reaction ratewith that of a control (i.e. with no test compound). IC₅₀ values werecalculated from a series of percent inhibition values determined at arange of inhibitor concentrations using software routines as implementedin the GraphPad Prism software package.

PDGFRβ Kinase Assay

This was done as described for PDGFGRα except that PDGFRβ (Invitrogen,11 nM) was used.

As shown in Tables 1 and 2, compounds of formula Ia exhibit inhibitoryactivity in one or more of the aforementioned assays when evaluated atconcentrations≦10 μM.

TABLE 1 Enzymatic Activity cMET cKIT KDR FMS PDGFRa PDGFRb ExampleEnzyme Enzyme Enzyme Enzyme Enzyme Enzyme # Assay Assay Assay AssayAssay Assay 1 +++ ++ ++ NT +++ ++ 3 + NT ++ NT ++ + 4 + ++ ++ +++ + + 5+++ NT NT NT NT NT 6 ++ + +++ ++ ++ + 7 +++ + ++ +++ ++ + 8 + NT NT NTNT NT 10 ++ NT NT NT NT NT 11 ++ NT NT NT NT NT 12 +++ +++ + +++ +++ +++13 + NT NT NT NT NT 14 ++ NT NT NT NT NT 15 ++ NT NT NT NT NT 16 +++++ + +++ ++ + 17 + ++ + +++ + + 18 ++ NT NT NT NT NT 19 +++ NT NT NT NTNT 20 ++ NT NT NT NT NT 21 ++ ++ ++ NT ++ + 22 ++ ++ ++ +++ ++ ++ 23++ + + ++ + + 24 ++ NT NT NT NT NT 25 ++ NT NT NT NT NT 26 + NT NT NT NTNT 27 ++ NT NT NT NT NT 28 + NT NT NT NT NT 29 ++ NT NT NT NT NT 30 ++++++ NT NT ++ + 31 +++ NT NT NT NT NT 32 ++ NT + ++ NT NT 33 ++ NT NT NTNT NT 34 ++ NT NT NT NT NT 35 ++ NT NT NT NT NT 36 ++ NT NT NT NT NT 38++ NT + + NT NT 39 NT NT NT NT +++ ++ 40 +++ +++ +++ NT ++ + 41 ++ ++ +++++ ++ + 42 +++ +++ + NT +++ + 43 ++ ++ + +++ +++ ++ 44 ++ ++ + +++ ++++++ 45 +++ +++ ++ NT + + 46 +++ +++ ++ NT +++ +++ 47 +++ +++ ++ NT +++ +48 + ++ ++ + + + 49 +++ +++ ++ ++ + + 50 +++ +++ +++ NT ++ + 51 +++ +++++ +++ ++ ++ 52 + NT + + NT NT 53 + NT + + NT NT 54 + NT + + NT NT55 + + + + + + 58 + + + NT + NT 59 +++ NT + +++ NT NT 60 ++ NT NT NT NTNT + less than 10 μM activity ++ less than 2 μM activity +++ less than200 nM activity NT not tested

TABLE 2 Cellular Acitivity EBC1 M-NFS-60 Cell Cell HUVEC Mo-7e Example #Proliferation Proliferation pKDR pKIT 6 + NT NT NT 7 +++ NT ++ NT 12 ++++++ +++ ++ 16 + NT NT NT 19 ++ NT NT NT 20 ++ NT NT NT 21 ++ NT NT NT 22++ NT NT NT 23 ++ NT NT NT 30 ++ NT NT NT 31 ++ NT NT NT 40 +++ NT ++ NT41 NT + NT NT 42 +++ NT NT ++ 44 NT +++ ++ +++ 45 +++ NT NT +++ 46 +++NT NT NT 47 +++ NT NT NT 49 ++ NT NT NT 50 +++ NT NT NT 51 ++ NT NT NT +less than 10 μM activity ++ less than 2 μM activity +++ less than 200 nMactivity NT not tested

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain, usingno more than routine experimentation, numerous equivalents to thespecific embodiments described specifically in this disclosure. Suchequivalents are intended to be encompassed in the scope of the followingclaims.

What is claimed is:
 1. A compound of formula Ia

and pharmaceutically acceptable salts, hydrates, solvates, and tautomersthereof; wherein Q1 and Q2 are each individually and independentlyselected from the group consisting of N and CH and wherein at least oneof Q1 and Q2 are N; each D is individually taken from the groupconsisting of C, CH, C—R20, N—Z3, N, and O, such that the resultant ringis taken from the group consisting of pyrazolyl, isoxazolyl, triazolyland imidazolyl; V is NR4, or

each Q5 is C(Z2B)₂; W is —[C(R13)R14]_(m)-, —[C(R13)R14]_(m)NR4-, orNR4; A is selected from the group consisting of phenyl, pyridinyl,thienyl, indanyl, tetrahydronapthyl, naphthyl, pyrazinyl, pyridazinyl,triazinyl, and pyrimidinyl; when A has one or more substitutablesp2-hybridized carbon atoms, each respective sp2 hybridized carbon atommay be optionally substituted with a Z1B substituent; when A has one ormore substitutable sp3-hybridized carbon atoms, each respective sp3hybridized carbon atom may be optionally substituted with a Z2Bsubstituent; each Z1B is independently and individually selected fromthe group consisting of hydrogen, halogen, C1-6alkyl, branchedC3-C7alkyl, fluoroC1-C6alkyl wherein the alkyl moiety can be partiallyor fully fluorinated, C1-C6alkoxy, fluoroC1-C6alkoxy wherein the alkylmoiety can be partially or fully fluorinated, and —(CH₂)_(n)CN; each Z2Bis independently and individually selected from the group consisting ofhydrogen, C1-C6alkyl, and branched C3-C7alkyl; each Z3 is independentlyand individually selected from the group consisting of C1-C6alkyl,hydrogen, branched C3-C7alkyl, C3-C8cycloalkyl, fluoroC1-C6alkyl whereinthe alkyl moiety can be partially or fully fluorinated,hydroxyC2-C6alkyl-, R5C(O)(CH₂)_(n)—, (R4)₂NC(O)C1-C6alkyl-,R8C(O)N(R4)(CH₂)_(q)—, —(CH₂)_(q)CN, —(CH₂)_(q)R5, and —(CH₂)_(q)N(R4)₂;each R2 is selected from the group consisting of hydrogen,R17-substituted aryl-, C1-C6alkyl, branched C3-C8alkyl, R19 substitutedC3-C8cycloalkyl-, and fluoroC1-C6alkyl- wherein the alkyl is fully orpartially fluorinated; wherein each R3 is independently and individuallyselected from the group consisting of hydrogen, C1-C6alkyl, branchedC3-C7alkyl, and C3-C8cycloalkyl; each R4 is independently andindividually selected from the group consisting of hydrogen, C1-C6alkyl,hydroxyC1-C6alkyl-, dihydroxyC1-C6alkyl-, C1-C6alkoxyC1-C6alkyl-,branched C3-C7alkyl, hydroxyl substituted branched C3-C6alkyl-,C1-C6alkoxy branched C3-C6alkyl-, dihydroxy substituted branchedC3-C6alkyl-, —(CH₂)_(p)N(R7)₂, —(CH₂)_(p)R5, —(CH₂)_(p)C(O)N(R7)₂,—(CH₂)_(n)C(O)R5, —(CH₂)_(n)C(O)OR3, and R19 substitutedC3-C8cycloalkyl-; each R5 is independently and individually selectedfrom the group consisting of

and wherein the symbol (##) is the point of attachment to respective R4,R7, R8, R20 or Z3 moieties containing a R5 moiety; each R7 isindependently and individually selected from the group consisting ofhydrogen, C1-C6alkyl, hydroxyC2-C6alkyl-, dihydroxyC2-C6alkyl-,C1-C6alkoxyC2-C6alkyl-, branched C3-C7alkyl, hydroxy substitutedbranched C3-C6alkyl-, C1-C6alkoxy branched C3-C6alkyl-, dihydroxysubstituted branched C3-C6alkyl-, —(CH₂)_(q)R5, —(CH₂)_(n)C(O)R5,—(CH₂)_(n)C(O)OR3, R19 substituted C3-C8cycloalkyl- and —(CH₂)_(n)R17;each R8 is independently and individually selected from the groupconsisting of C1-C6alkyl, branched C3-C7alkyl, fluoroC1-C6alkyl- whereinthe alkyl moiety is partially or fully fluorinated, R19 substitutedC3-C8cycloalkyl-, phenyl, phenylC1-C6alkyl-, OH, C1-C6alkoxy, —N(R3)₂,—N(R4)₂, and R5; each R10 is independently and individually selectedfrom the group consisting of —CO₂H, —CO₂C1-C6alkyl, —C(O)N(R4)₂, OH,C1-C6alkoxy, and —N(R4)₂; R13 and R14 are each individually andindependently selected from the group consisting of hydrogen,C1-C6alkyl, branched C3-C8alkyl, fluoroC1-C6alkyl- wherein the alkyl isfully or partially fluorinated, hydroxyl substituted C1-C6alkyl-,C1-C6alkoxy substituted C1-C6alkyl-, hydroxyl substituted branchedC3-C8alkyl-, and alkoxy substituted branched C3-C8alkyl; each R16 isindependently and individually selected from the group consisting ofhydrogen, C1-C6alkyl, branched C3-C7alkyl, R19 substitutedC3-C8cycloalkyl-, halogen, fluoroC1-C6alkyl- wherein the alkyl moietycan be partially or fully fluorinated, cyano, hydroxyl, C1-C6alkoxy,fluoroC1-C6alkoxy- wherein the alkyl moiety can be partially or fullyfluorinated, —N(R3)₂, —N(R4)₂, R3 substituted C2-C3alkynyl- and nitro;each R17 is independently and individually selected from the groupconsisting of hydrogen, C1-C6alkyl, branched C3-C7alkyl,hydroxyC2-C6alkyl-, R19 substituted C3-C8cycloalkyl-, halogen,fluoroC1-C6alkyl- wherein the alkyl moiety can be partially or fullyfluorinated, cyano, hydroxyl, C1-C6alkoxy, fluoroC1-C6alkoxy- whereinthe alkyl moiety can be partially or fully fluorinated, —N(R3)₂,—N(R4)₂, and nitro; each R19 is independently and individually selectedfrom the group consisting of hydrogen, OH and C1-C6alkyl; each R20 isindependently and individually selected from the group consisting ofhydrogen, C1-C6alkyl, branched C3-C7alkyl, R19 substitutedC3-C8cycloalkyl-, halogen, fluoroC1-C6alkyl- wherein the alkyl moietycan be partially or fully fluorinated, cyano, hydroxyl,hydroxyC1-C6alkyl-, C1-C6alkoxyC1-C6alkyl-, C1-C6alkoxy,fluoroC1-C6alkoxy- wherein the alkyl moiety can be partially or fullyfluorinated, —N(R3)₂, —N(R4)₂, —(CH₂)_(n)R5, —(CH₂)_(n)N(R3)C(O)R3,—(CH₂)_(n)C(O)N(R3)₂ and nitro; each m is independently and individually1-3, each n is independently and individually 0-6; each p isindependently and individually 1-4; each q is independently andindividually 2-6; each v is independently and individually 1 or 2; eachx is independently and individually 0-2; stereoisomers, regioisomers andtautomers of such compounds.
 2. A compound of claim 1 wherein

is selected from the group consisting of wherein the symbol (**)indicates the point of attachment to the heteroaryl Q1, Q2 containingring.
 3. A compound of claim 2 having formula Ic


4. A compound of claim 2 having formula Id


5. A compound of claim 2 having formula Ie


6. A compound of claim 2 having formula Io


7. A compound of claim 2 having formula Ip


8. A compound of claim 2 having formula Iq


9. A compound of claim 2 having formula Iaa


10. A compound of claim 2 having formula Ibb


11. A compound of claim 2 having formula Icc


12. A compound selected from the group consisting ofN-(2,3-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,N-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,N-benzyl-N′-(2,3-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)cyclopropane-1,1-dicarboxamide,N-benzyl-N′-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)cyclopropane-1,1-dicarboxamide,N-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-phenylcyclopropane-1,1-dicarboxamide,N-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(3-(trifluoromethyl)phenyl)cyclopropane-1,1-dicarboxamide,N-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,N-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(4-methoxyphenyl)cyclopropane-1,1-dicarboxamide,N-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(3-methoxyphenyl)cyclopropane-1,1-dicarboxamide,N-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(3-fluorophenyl)cyclopropane-1,1-dicarboxamide,N-(4-fluorophenyl)-N′-(3-methyl-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)cyclopropane-1,1-dicarboxamide,1-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea,N-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(pyridin-4-yl)cyclopropane-1,1-dicarboxamide,N-(3-fluoro-4-(2-(1-methyl-1,4-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(pyridin-3-yl)cyclopropane-1,1-dicarboxamide,N-(3-chlorobenzyl)-N′-(3-fluoro-4-(2-(1-methyl-1H-1-pyrazol-4-yl)pyridin-4-yloxy)phenyl)cyclopropane-1,1-dicarboxamide,N-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-((S)-1-phenylethyl)cyclopropane-1,1-dicarboxamide,N-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-((R)-1-phenylethyl)cyclopropane-1,1-dicarboxamide,N-(4-fluorobenzyl)-N′-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)cyclopropane-1,1-dicarboxamide,N-(4-(2-(1-ethyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,N-(3-fluoro-4-(2-(1-propyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,N-(3-fluoro-4-(2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,N-(4-chlorophenyl)-N′-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)cyclopropane-1,1-dicarboxamide,N-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-p-tolylcyclopropane-1,1-dicarboxamide,N-(3,4-difluorophenyl)-N′-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)cyclopropane-1,1-dicarboxamide,N-(2-fluoro-4-(2-(1-methyl-1,4-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(4-(trifluoromethyl)phenyl)cyclopropane-1,1-dicarboxamide,N-(3-cyano-4-fluorophenyl)-N′-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)cyclopropane-1,1-dicarboxamide,N-(2,4-difluorophenyl)-N′-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)cyclopropane-1,1-dicarboxamide,N-(4-cyanophenyl)-N′-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)cyclopropane-1,1-dicarboxamide,N-(2-chloro-4-fluorophenyl)-N′-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)cyclopropane-1,1-dicarboxamide,N-(3-chloro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,N-(4-(2-(1H-pyrazol-4-yl)pyridin-4-yloxy)-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,N-(2-fluoro-3-methyl-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,N-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-((S)-1-(4-fluorophenyl)ethyl)cyclopropane-1,1-dicarboxamidehydrochloride,N-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-((S)-1-(4-fluorophenyl)propyl)cyclopropane-1,1-dicarboxamidehydrochloride,N-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(thiophen-2-yl)cyclopropane-1,1-dicarboxamide,N-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-((R)-1-(4-fluorophenyl)-2-methoxyethyl)cyclopropane-1,1-dicarboxamide,N-(4-fluorophenyl)-N′-(4-(2-(4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yloxy)phenyl)cyclopropane-1,1-dicarboxamide,2-(4-fluorophenyl)-N-(4-(2-(4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yloxy)phenylcarbamoyl)acetamide,N-(2,5-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,N-(2,5-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenylcarbamoyl)-2-(4-fluorophenyl)acetamide,N-(2,3-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenylcarbamoyl)-2-(4-fluorophenyl)acetamide,N-(2,5-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-phenylcyclopropane-1,1-dicarboxamide,N-(5-chloro-2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenylcarbamoyl)-2-(4-fluorophenyl)acetamide,N-(5-chloro-2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,N-(3,5-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenylcarbamoyl)-2-(4-fluorophenyl)acetamide,N-(4-(2-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,N-(4-fluorophenyl)-N′-(4-(2-(4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yloxy)phenyl)cyclopropane-1,1-dicarboxamide,N-(2-fluoro-5-methyl-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,N-(2,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,N-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)-N-methylcyclopropane-1,1-dicarboxamide,N-(2-fluoro-4-(2-(3-methylisoxazol-5-yl)pyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,N-(4-(2-(1H-1,2,3-triazol-4-yl)pyridin-4-yloxy)-2-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,and pharmaceutically acceptable salts and tautomers thereof.
 13. Amethod of treating mammalian disease wherein the disease etiology orprogression is at least partially mediated by the kinase activity ofPDGFR-α kinase, PDGFRβ kinase, c-KIT kinase, cFMS kinase, or c-METkinase and oncogenic forms, aberrant fusion proteins and polymorphsthereof, comprising the step of administering to the mammal a compoundof claim
 1. 14. A method of claim 13 wherein said kinase is c-METprotein kinase, and any fusion protein, mutation and polymorphs thereof.15. A pharmaceutical composition comprising a compound of claim 1,together with a pharmaceutically acceptable carrier, optionallycontaining an additive selected from the group consisting of adjuvants,excipients, diluents, and stabilizers.
 16. A method of treating anindividual suffering from a condition selected from the group consistingof metabolic diseases, neurodegenerative diseases, retinopathies,diabetic retinopathy, and age-related macular degeneration, rheumatoidarthritis, asthma, and chronic obstructive pulmonary disease, comprisingthe step of administering to such individual a compound of claim
 1. 17.A method of treating an individual suffering from a condition selectedfrom the group consisting of cancer, solid tumors, melanomas,glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lungcancers, breast cancers, renal cancers, hepatic cancers, cervicalcarcinomas, metastasis of primary tumor sites, myeloproliferativediseases, chronic myelogenous leukemia, leukemias, papillary thyroidcarcinoma, non-small cell lung cancer, mesothelioma, hypereosinophilicsyndrome, gastrointestinal stromal tumors, colonic cancers,hypereosinophilic syndrome, mastocytosis, or mast cell leukemia,comprising the step of administering to such individual a compound ofclaim
 1. 18. The method of claim 16, said compound being administered bya method selected from the group consisting of oral, parenteral,inhalation, and subcutaneous.
 19. The method of claim 17, said compoundbeing administered by a method selected from the group consisting oforal, parenteral, inhalation, and subcutaneous.